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Добірка наукової літератури з теми "Inhibitor of HDAC6"

Автор: Grafiati

Опубліковано: 14 березня 2023

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Статті в журналах з теми "Inhibitor of HDAC6"

Stubbs, Matthew C., Won-Il Kim, Tina Davis, Jun Qi, James Bradner, Andrew L. Kung, and Scott A. Armstrong. "Selective Inhibition of HDAC1 and HDAC2 Is a Potential Therapeutic Option for B-All." Blood 116, no. 21 (November 19, 2010): 2900. http://dx.doi.org/10.1182/blood.v116.21.2900.2900.

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Abstract Abstract 2900 Histone deacetylase inhibitors (HDACi) have emerged as potent anticancer agents, and could open the door for future epigenetic therapies. As our understanding of the importance of epigenetic histone modifications in B-cell acute lymphoblastic leukemia (B-ALL) increases, we hypothesized that HDACi could potentially be a useful therapeutic option. The pan-HDAC inhibitor LAQ824 (Novartis) was toxic to B-ALLs in low nM concentrations in vitro, and treated cells had increased p21 and DNA damage response as indicated by increased γH2A.X protein levels. Additionally, the related compound panobinostat (Novartis) reduced leukemic burden from B-ALL patient samples in primary xenograft models, indicating that pan-HDAC inhibition is a putative B-ALL therapeutic option. To determine HDAC isoform-specific effects, we used a high throughput assay that exposed B-ALL cell lines to a panel of HDAC inhibitors. This screen indicated that tubacin, an HDAC6 specific inhibitor, cannot inhibit B-ALL cell growth within a dose range where HDAC6 is the only HDAC targeted. This finding was further validated using another HDAC6 specific inhibitor, WT-161. The screen also indicated that benzimide compounds such as MGCD-0103 (MethylGene) and MS-275 (Entinostat, Syndax) which only target class I HDACs (HDAC1-3) effectively inhibited growth in the cell lines. These data indicate that inhibiting the class I HDACs is sufficient to suppress B-ALL cell line growth. To determine which HDACs are necessary for cell viability, we lentivirally introduced isoform-specific shRNAs into our ALL cell lines. Knockdown of HDAC1 or HDAC2 resulted in p21 induction, slowed growth rate and resulted in a modest increase in apoptosis. Knockdown of HDAC3 lead to increased p21 and γH2A.X protein levels, along with induction of apoptosis, closely mimicking the results of pan-HDAC inhibitor treatment of the cells. Although depletion of HDAC3 had a more immediate impact on B-ALL viability by comparison to HDAC1/2, concerns about the contribution of HDAC3 inhibition to toxicity led us to further investigate whether specific inhibition of HDAC1/2 might be efficacious in B-ALL. Treatment of B-ALL cells with Merck 60, a tool compound with selectivity for HDAC1/2, was efficacious against was effective against B-ALL lines in the low to mid nM range. The kinetics of growth suppression were slower with this compound than with the pan-HDAC inhibitors. Using this compound, the ALL lines required 72 hours of exposure before cell growth was diminished, and apoptosis ensued. This may be due to the increased time necessary to accumulate acetylated histone marks as observable by western blot (18 hours for Merck 60 vs. 2–4 hours for LAQ824). Increased levels of p21 and γH2A.X were also observed. Interestingly, AML cell lines were much less sensitive to the HDAC1/2 specific inhibitor than were the B-ALL lines (roughly 5–10 fold), whereas pan-HDAC inhibitors were equally effective against AML and ALL. Additionally, non-hematopoietic tumor derived cell lines were insensitive to Merck 60, with EC50 values exceeding 20μM. Our findings indicate that pan-HDAC and class I specific HDAC inhibitors are possible therapeutic options for B-ALL. In contrast to most other cancer cell types studied, selective inhibition of HDAC1 and HDAC2 was sufficient to induce apoptosis in B-ALL lines. Together, these results suggest that small molecules specifically targeting HDAC1/2 may have therapeutic utility in B-ALL, and may provide improved therapeutic index by comparison to pan-HDAC or class I HDAC inhibitors that also target HDAC3. Disclosures: No relevant conflicts of interest to declare.

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Khan, Nagma, Michael Jeffers, Sampath Kumar, Craig Hackett, Ferenc Boldog, Nicholai Khramtsov, Xiaozhong Qian, et al. "Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors." Biochemical Journal 409, no. 2 (December 21, 2007): 581–89. http://dx.doi.org/10.1042/bj20070779.

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The human HDAC (histone deacetylase) family, a well-validated anticancer target, plays a key role in the control of gene expression through regulation of transcription. While HDACs can be subdivided into three main classes, the class I, class II and class III HDACs (sirtuins), it is presently unclear whether inhibiting multiple HDACs using pan-HDAC inhibitors, or targeting specific isoforms that show aberrant levels in tumours, will prove more effective as an anticancer strategy in the clinic. To address the above issues, we have tested a number of clinically relevant HDACis (HDAC inhibitors) against a panel of rhHDAC (recombinant human HDAC) isoforms. Eight rhHDACs were expressed using a baculoviral system, and a Fluor de Lys™ (Biomol International) HDAC assay was optimized for each purified isoform. The potency and selectivity of ten HDACs on class I isoforms (rhHDAC1, rhHDAC2, rhHDAC3 and rhHDAC8) and class II HDAC isoforms (rhHDAC4, rhHDAC6, rhHDAC7 and rhHDAC9) was determined. MS-275 was HDAC1-selective, MGCD0103 was HDAC1- and HDAC2-selective, apicidin was HDAC2- and HDAC3-selective and valproic acid was a specific inhibitor of class I HDACs. The hydroxamic acid-derived compounds (trichostatin A, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat) were potent pan-HDAC inhibitors. The growth-inhibitory effect of the HDACis on HeLa cells showed that both pan-HDAC and class-I-specific inhibitors inhibited cell growth. The results also showed that both pan-HDAC and class-I-specific inhibitor treatment resulted in increased acetylation of histones, but only pan-HDAC inhibitor treatment resulted in increased tubulin acetylation, which is in agreement with their activity towards the HDAC6 isoform.

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Cao, Jiangying, Wei Zhao, Chunlong Zhao, Qian Liu, Shunda Li, Guozhen Zhang, C. James Chou, and Yingjie Zhang. "Development of a Bestatin-SAHA Hybrid with Dual Inhibitory Activity against APN and HDAC." Molecules 25, no. 21 (October 28, 2020): 4991. http://dx.doi.org/10.3390/molecules25214991.

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With five histone deacetylase (HDAC) inhibitors approved for cancer treatment, proteolysis-targeting chimeras (PROTACs) for degradation of HDAC are emerging as an alternative strategy for HDAC-targeted therapeutic intervention. Herein, three bestatin-based hydroxamic acids (P1, P2 and P3) were designed, synthesized and biologically evaluated to see if they could work as HDAC degrader by recruiting cellular inhibitor of apoptosis protein 1 (cIAP1) E3 ubiquitin ligase. Among the three compounds, the bestatin-SAHA hybrid P1 exhibited comparable even more potent inhibitory activity against HDAC1, HDAC6 and HDAC8 relative to the approved HDAC inhibitor SAHA. It is worth noting that although P1 could not lead to intracellular HDAC degradation after 6 h of treatment, it could dramatically decrease the intracellular levels of HDAC1, HDAC6 and HDAC8 after 24 h of treatment. Intriguingly, the similar phenomenon was also observed in the HDAC inhibitor SAHA. Cotreatment with proteasome inhibitor bortezomib could not reverse the HDAC decreasing effects of P1 and SAHA, confirming that their HDAC decreasing effects were not due to protein degradation. Moreover, all three bestatin-based hydroxamic acids P1, P2 and P3 exhibited more potent aminopeptidase N (APN, CD13) inhibitory activities than the approved APN inhibitor bestatin, which translated to their superior anti-angiogenic activities. Taken together, a novel bestatin-SAHA hybrid was developed, which worked as a potent APN and HDAC dual inhibitor instead of a PROTAC.

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Skov, Vibe, Thomas Stauffer Larsen, Mads Thomassen, Caroline Riley, Morten Krogh Jensen, Ole Weis Bjerrum, Torben A. Kruse, and Hans Carl Hasselbalch. "Increased Gene Expression of Histone Deacetylases In Patients with Philadelphia-Negative Chronic Myeloproliferative Neoplasms." Blood 116, no. 21 (November 19, 2010): 4119. http://dx.doi.org/10.1182/blood.v116.21.4119.4119.

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Abstract Abstract 4119 Introduction: Several new treatment strategies within the Philadelphia-negative chronic myeloproliferative neoplasms CMPNs are beeing explored, among these, agents belonging to the class of HDAC-inhibitors, including givinostat (ITF2357) and vorinostat (suberoylanilide hydroxamic acid (SAHA)). These agents are inhibitors of class I and II HDAC enzymes, promoting cell-cycle arrest and apoptosis of cancer cells. Recently, enhanced histone deacetylase (HDAC) enzyme activity has been found in CD34+ cells from patients with primary myelofibrosis (PMF), enzyme activity levels highly exceeding those recorded in essential thrombocythemia (ET) and polycythemia vera (PV). The raised levels correlated to the degree of splenomegaly, suggesting that HDAC might be recruited as ET or PV progresses into myelofibrosis or PMF progresses into a more advanced stage. In order to further describe HDACs in CMPNs, we have assessed gene expression of several HDACs in a larger cohort of patients with ET, PV and PMF. Patients and Methods: Gene expression microarray studies have been performed on control subjects (n=21) and patients with ET (n =19), PV (n=41), and PMF (n=9). Most patients were studied on cytoreductive therapy, which for the large majority included hydroxyurea. Gene expression profiles were generated using Affymetrix HG-U133 2.0 Plus microarrays recognizing 54675 probe sets (38.500 genes). Total RNA was purified from whole blood and amplified to biotin-labeled aRNA and hybridized to microarray chips. Results: We identified 20439, 25307, 17417, and 25421 probe sets which were differentially expressed between controls and patients with ET, PV, PMF, and CPMNs as a whole, respectively (false discovery rate (FDR) adjusted p values < 0.05). Several HDAC-genes were significantly deregulated. In ET patients upregulated genes included HDAC5, HDAC9 and downregulated genes HDAC1, HDAC4, HDAC7. In PV-patients HDAC4, HDAC5, HDAC6, HDAC9, and HDAC11 genes were upregulated, and HDAC1, HDAC7, HDAC9, and HDAC11 genes were downregulated. In PMF -patients HDAC4, HDAC6, HDAC9, and HDAC11 genes were upregulated, and HDAC1 and HDAC7 were downregulated. Compared to controls the CMPN-patients as a group exhibited upregulation of HDAC4, HDAC5, HDAC6, HDAC9, and HDAC11 genes. The HDAC genes 9 and 11 were significantly upregulated in both ET, PV, PMF, and CMPNs as a whole, the highest values being recorded in patients with ET, PMF, and CMPNs as compared to controls. In regard to HDAC9 gene expression, the fold changes (FC) were 1.3, 1.2, 1.3, and 1.3 for ET, PV, PMF, and CMPNs, respectively; for HDAC11 the highest values were recorded in patients with ET with the following FCs 1.2, 1.1, 1.1, 1.1 for ET, PV, PMF, and CMPNs, respectively; FDR adjusted p values < 0.05). Within patients, the HDAC6-gene was also differentially expressed with the highest levels being recorded in patients with PMF (FC 1.2, FDR adjusted p values < 0.01). When comparing non-PMF-patients with PMF-patients, a significant upregulation of the HDAC2-gene was found in PMF patients (FC 1.5, FDR adjusted p-value=0.007), whereas the HDAC7-gene was significantly downregulated (FC -1.3, FDR adjusted p-value=0,001. Discussion and Conclusions: Using global gene expression profiling of whole-blood from patients with CMPNs, we have found a pronounced deregulation of HDAC-genes, involving significant upregulation of the HDAC-genes 9 and 11 with the highest expression levels being found in patients with ET, in PMF (HDAC9) and in CMPNs both HDAC9 and HDAC11. Furthermore, we have identified that the HDAC-6 gene is progressively expressed in patients with ET, PV, and PMF reflecting a steady accumulation of abnormally expressed HDAC-6 during disease evolution. Our results lend further support to HDACs as important epigenetic targets in the future treatment of patients with CMPNs. Since the highest expression levels of HDAC-genes was recorded in ET (HDACs 9 and 11), in PMF (HDAC9) and in the whole CMPN-group both HDACs 9 and 11, their downregulation by HDAC-inhibitors might be associated with decreased disease activity including reduction of splenomegaly in MF. Preliminary data indicate that enlarged spleens are diminished in subsets of patients during treatment with HDAC-inhibitors. Studies are in progress on the impact of vorinostat on global gene expression profiling, including HDAC- gene expression subclasses in patients with CMPNs. Disclosures: No relevant conflicts of interest to declare.

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Bui, Hue Thi Buu, Phuong Hong Nguyen, Quan Minh Pham, Hoa Phuong Tran, De Quang Tran, Hosun Jung, Quang Vinh Hong, et al. "Target Design of Novel Histone Deacetylase 6 Selective Inhibitors with 2-Mercaptoquinazolinone as the Cap Moiety." Molecules 27, no. 7 (March 28, 2022): 2204. http://dx.doi.org/10.3390/molecules27072204.

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Epigenetic alterations found in all human cancers are promising targets for anticancer therapy. In this sense, histone deacetylase inhibitors (HDACIs) are interesting anticancer agents that play an important role in the epigenetic regulation of cancer cells. Here, we report 15 novel hydroxamic acid-based histone deacetylase inhibitors with quinazolinone core structures. Five compounds exhibited antiproliferative activity with IC50 values of 3.4–37.8 µM. Compound 8 with a 2-mercaptoquinazolinone cap moiety displayed the highest antiproliferative efficacy against MCF-7 cells. For the HDAC6 target selectivity study, compound 8 displayed an IC50 value of 2.3 µM, which is 29.3 times higher than those of HDAC3, HDAC4, HDAC8, and HDAC11. Western blot assay proved that compound 8 strongly inhibited tubulin acetylation, a substrate of HDAC6. Compound 8 also displayed stronger inhibition activity against HDAC11 than the control drug Belinostat. The inhibitory mechanism of action of compound 8 on HDAC enzymes was then explored using molecular docking study. The data revealed a high binding affinity (−7.92 kcal/mol) of compound 8 toward HDAC6. In addition, dock pose analysis also proved that compound 8 might serve as a potent inhibitor of HDAC11.

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Varricchio, Lilian, Carmela Dell'Aversana, Angela Nebbioso, Giovanni Migliaccio, Lucia Altucci, James J. Bieker, and Anna Rita F. Migliaccio. "Identification of a New Functional HDAC Complex Composed by HDAC5, GATA1 and EKLF in Human Erythroid Cells." Blood 120, no. 21 (November 16, 2012): 979. http://dx.doi.org/10.1182/blood.v120.21.979.979.

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Abstract Abstract 979 Histone deacetylation, the reaction that maintains chromatin in a condensed configuration preventing gene expression, is catalyzed by the histone deacetylase (HDAC) superfamily. The human HDAC family includes 18 different isoforms classified on the basis of their sequence homology to HDACs from Saccharomyces Cerevisiae into class I (HDAC1, −2, −3, and −8), IIa (HDAC4, −5, −7, and −9), IIb (HDAC6 and −10) and IV (HDAC11). Class I HDACs bind the DNA directly while class IIa HDACs shuffles other proteins between nucleus and cytoplasm. While the role of individual class I HDACs in erythropoiesis is starting to emerge, that of class IIa and b HDACs is still largely unknown. To clarify the role played by class IIa HDACs in the control of human erythropoiesis, an extensive analysis of expression, activity, and function of different classes of HDACs during the maturation of erythroblasts derived in vitro from adult blood or cord blood was performed. HDACs expression/activity. Erythroid maturation was associated with increased expression of class I HDACs (both mRNA and protein) which, in the case of HDAC1, was also associated with increased enzymatic activity and association with its NuRD partner GATA1. By contrast, reductions either in expression (HDAC4) or activity (HDAC5) of class IIa HDACs were observed with maturation. In addition, GATA1 and EKLF were consistently found associated in human erythroblasts but EKLF was not found associated with HDAC1. The extent of nuclear-cytoplasmic trafficking of class I (HDAC1 and 2) and IIa (HDAC4 and 5) and of the transcription factors EKLF and GATA1 in response to EPO was determined. HDAC2/EKLF/GATA1 and HDAC4 were found constitutively present in the nucleus and in the cytoplasm, respectively. By contrast, the nuclear concentration of HDAC1 increased while that of HDAC5 and of GATA1fl decreased upon stimulation with EPO. The last two observations suggested that HDAC5, GATA1 and EKLF might be associated in a complex. Identification of the HDAC5/EKLF/GATA1 complex. A series of IPs followed by WB experiments showed that HDAC5 was consistently associated with EKLF and GATA1 and conversely, both GATA1 (preferentially GATA1fl over GATA1s) and EKLF were consistently associated with HDAC5 (Fig 1A and not shown). Interestingly also pERK was detected in IPs with HDAC5, EKLF and GATA1 antibodies. These results indicate that in erythroid cells HDAC5 forms a complex with GATA1, EKLF and pERK. Identification of the biological activity of the HDAC5/GATA1/EKLF/pERK complex. The association between GATA1/EKLF was greater in cells generated with cord blood (which express high HbF levels) than in those derived from adult blood and their association decreased with maturation, suggesting that the complex may regulate HbF expression. To confirm this hypothesis, HDAC5/GATA1 association and γ/(γ+ β) mRNA ratios were determined in erythroid cells induced to mature in the presence of a pan-class II-specific (APHA9, ID50=20 μM for HDAC4) HDAC inhibitor (HDACi) (Fig 1B)1. Cells exposed in parallel to the class I/IIa-specific (UBHA24, ID50 =0.2 and 0.6 μM for HDAC1 and HDAC4, respectively) HDACi, were used as control. Exposure to APHA9 reduced the association between GATA1 and HDAC5 and increased γ/(γ + β) mRNA expression ratio, while this association was not affected by exposure to the class I/II HDACi which, as expected, also increased γ/(γ+ β) mRNA ratio. Conclusions. These data identify a new HDAC complex formed by HDAC5, EKLF and GATA1 that regulates γ/(γ + β) ratio. We hypothesize that the biological role of this new complex is to shuffle GATA1 and EKLF from the cytoplasm to the nucleus, making them able to engage into the NuRD and Sin3A complex respectively, and that inhibition of the activity of this complex affects γ-globin expression indirectly by limiting the amount of GATA1and EKLF available to associate with NuRD and Sin3A. Disclosures: No relevant conflicts of interest to declare.

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Kraft, Fabian B., Maria Hanl, Felix Feller, Linda Schäker-Hübner, and Finn K. Hansen. "Photocaged Histone Deacetylase Inhibitors as Prodrugs in Targeted Cancer Therapy." Pharmaceuticals 16, no. 3 (February 25, 2023): 356. http://dx.doi.org/10.3390/ph16030356.

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Histone deacetylases (HDACs) play a key role in the control of transcription, cell proliferation, and migration. FDA-approved histone deacetylase inhibitors (HDACi) demonstrate clinical efficacy in the treatment of different T-cell lymphomas and multiple myeloma. However, due to unselective inhibition, they display a wide range of adverse effects. One approach to avoiding off-target effects is the use of prodrugs enabling a controlled release of the inhibitor in the target tissue. Herein, we describe the synthesis and biological evaluation of HDACi prodrugs with photo-cleavable protecting groups masking the zinc-binding group of the established HDACi DDK137 (I) and VK1 (II). Initial decaging experiments confirmed that the photocaged HDACi pc-I could be deprotected to its parent inhibitor I. In HDAC inhibition assays, pc-I displayed only low inhibitory activity against HDAC1 and HDAC6. After irradiation with light, the inhibitory activity of pc-I strongly increased. Subsequent MTT viability assays, whole-cell HDAC inhibition assays, and immunoblot analysis confirmed the inactivity of pc-I at the cellular level. Upon irradiation, pc-I demonstrated pronounced HDAC inhibitory and antiproliferative activities which were comparable to the parent inhibitor I. Additionally, only phototreated pc-I was able to induce apoptosis in Annexin V/PI and caspase-Glo 3/7 assays, making pc-I a valuable tool for the development of light-activatable HDACi.

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Perez-Salvia, Montserrat, Aldaba Eneko, Vara Yosu, Fabre Myriam, Ferrer Cristina, Masdeu Carme, Zubia Aizpea, et al. "Efficacy of a New Small-Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) in Preclinical Models of B-Cell Lymphoma and Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 5383. http://dx.doi.org/10.1182/blood-2018-99-111578.

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Abstract Histone deacetylase 6 (HDAC6) is a protein modifier that is an increasingly attractive pharmacological target. Interestingly, the observation that the HDAC6 knock-out mouse is not lethal, in contrast to those undergoing complete loss of class I, II and III HDACs, suggests that specific HDAC6 inhibitors may be better tolerated than pan-HDAC inhibitors or drugs that target the other HDAC classes. In this regard, the compound ACY-1215 (Rocilinostat), the described selective HDAC6 inhibitors, is undergoing clinical trials for the treatment of multiple myeloma. Taking into account the previous information about HDAC6 inhibitor structures, the structural differences between HDAC6 and other HDAC isoforms and also the structural information of other developed HDAC inhibitors, we have previously designed and synthesized a new potential HDAC6 selective inhibitor, QTX125 with growth inhibitory effects in mantle cell lymphoma (MCL) cell lines, mouse models and ex vivo treatment of primary samples obtained from patients with MCL. Herein, we have extended these findings to show that the newly identified HDAC6 inhibitor QTX125 is also able to inhibit the growth of preclinical models of other B-cell lymphomas such as follicular lymphoma and Burkitt's cell lymphoma, but also of acute acute myeloid leukemia. In addition beyond a-tubulin, a well known HDAC6 target, we have developed a pharmacological and proteomic screening to identify other proteins modified by HDAC6 that can contribute to the described lymphoma and leukemia phenotypes. Disclosures Eneko: Quimatryx: Employment. Yosu:Quimatryx: Employment. Myriam:Oncomatryx: Employment. Cristina:Oncomatryx: Employment. González-Barca:Roche: Speakers Bureau; Celtrion: Consultancy; Gilead: Consultancy; janssen: Consultancy, Speakers Bureau. Fernando:Quimatryx: Consultancy.

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Lodish, Harvey F., and Peng Ji. "Enucleation." Blood 114, no. 22 (November 20, 2009): SCI—18—SCI—18. http://dx.doi.org/10.1182/blood.v114.22.sci-18.sci-18.

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Abstract Abstract SCI-18 Late erythroblasts undergo terminal cell cycle exit, chromatin condensation, and extrusion of the pycnotic nucleus via an asymmetric cell division, but the signaling pathways and genes involved in these last steps of erythropoiesis are not known. Last year we showed that enucleation of mouse fetal erythroblasts requires both Rac GTPases and mDia2, a downstream effector of Rho GTPases and a formin protein required for nucleation of unbranched actin filaments. Rac and mDia2 are required for formation of the cortical actin ring that apparently powers the separation between the membrane- enveloped nucleus and forming reticulocyte. In collaboration with Drs. Tzutzuy Ramirez Hernandez and Maki Murata-Hori of the Temasek Life Sciences Laboratory in Singapore we showed by time-lapse microscopy that extrusion of the nucleus begins with microtubule- dependent “pushing” of the nucleus to one pole of the cell. Final budding off of the nucleus happens quickly – requiring only about 5 minutes. By analyzing fractionated erythroblasts at all stages of differentiation we confirmed that the nucleus undergoes gradual condensation before being extruded out of the cytoplasm. To investigate how chromatin condensation affects condensation and enucleation, we treated cultured erythroblasts with trichostatin A, a pan-histone deacetylase inhibitor, and discovered that enucleation is completely blocked. We further demonstrated that HDAC1, HDAC2 and HDAC3 are highly expressed in erythroid cells. Using a retroviral system to express shRNAs in developing erythroblasts, we found that downregulation of HDAC2 partially blocked enucleation. We also focused on the role of HDAC6 on enucleation since previous reports showed that HDAC6 forms a complex with mDia2. We confirmed the interaction between HDAC6 and mDia2 and demonstrated that HDAC6 can deacetylate mDia2. This may activate mDia2 and eventually promote enucleation. Our hypothesis is that HDACs play two distinct roles in enucleation: HDAC1, HDAC2 and HDAC3 (class I HDACs) are necessary for the condensation of the chromatin which is required for enucleation; on the other hand, HDAC6 (class II HDAC) interacts with and deacetylates mDia2 to promote enucleation. Disclosures Lodish: Amgen: Consultancy, Research Funding.

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Hancock, Wayne W. "Epigenetic Regulation of Regulatory T-Cells: Impact on Autoimmunity and Graft Rejection." Blood 116, no. 21 (November 19, 2010): SCI—23—SCI—23. http://dx.doi.org/10.1182/blood.v116.21.sci-23.sci-23.

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Abstract Abstract SCI-23 Mutations of Foxp3, a transcription factor characteristic of T regulatory (Treg) cells, often cause lethal autoimmunity, leading to much research into how Foxp3+ Tregs control inflammatory and immune responses. This presentation will emphasize therapeutic aspects of our ongoing studies showing that the functions of Foxp3 are regulated by histone/protein deacetylases (HDAC), histone acetyltransferases (HAT), and DNA methyltransferases (DNMT), and for the sake of time will focus on the effects of HDAC inhibitors (HDACi). We have found that Foxp3 acetylation promotes DNA binding and can induce or suppress expression of multiple Foxp3-dependent genes in Tregs. Acetylation is catalyzed by specific HATs whose neutralization can diminish Treg function, with relevance to cancer and HIV, whereas use of selected HDAC inhibitors (HDACi) can increase acetylation and Treg suppression, with relevance to control of autoimmunity and transplant rejection. Many HDAC inhibitors (HDACi) were evaluated for their effects on Treg function. As class I-selective HDACi agents (e.g. benzamides) had little or no effect on Treg function, but pan-HDACi (e.g. hydroxymates) enhanced Treg function, we focused on class II HDACs. There are 2 class II subfamilies; class IIa members are thought to largely function in a tissue-specific manner through recruitment of other proteins since they display only weak catalytic activity, whereas class IIb family members display bona fide catalytic activity. We therefore analyzed class IIb members, of which HDAC6 is the best established and for which selective HDACi are available. HDAC6 exists in the cytoplasm and regulates acetylation of alpha-tubulin and other proteins, including HSP90. Blocking HDAC6 through the use of an HDAC6-specific inhibitor promotes HSP90 acetylation and release of HSP90 client proteins. Use of HDAC6 or HSP90 inhibitors increased Foxp3 expression and enhanced Treg function in vitro and in vivo, and could prevent, or treat pre-existing, autoimmunity in a Treg-dependent manner. We have also investigated the various class IIa family members, of which HDAC9 is of particular interest since its expression is increased 30-fold in Treg vs. regular T cells. HDAC9 decreases Foxp3 expression and function, and its neutralization promotes Treg survival by regulating expression of HSP70 and related HSPs. Our ongoing studies show that HDAC6 neutralization leads to acetylation of HSP90, release of HSF-1 and induction of HSP70, and also suggest that HDAC9 may regulate the acetylation and stabilization of HSF-1. Once produced, HSP70 can chaperone and promote Foxp3 nuclear translocation and function, such that the HDAC6 and HDAC9 pathways are closely intertwined with regard to control of Treg biology. In summary, acetylation, methylation and other epigenetic mechanisms in Tregs are being probed using genetic and pharmacologic approaches. Various currently approved drugs influence Foxp3-dependent Treg functions by affecting epigenetic mechanisms, and while additional HDAC-specific regulators are needed, a rationale is now in place for use of HDAC inhibitors as powerful tools to promote the development and functions of Foxp3+ Tregs in vitro and in vivo. Disclosures: No relevant conflicts of interest to declare.

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Дисертації з теми "Inhibitor of HDAC6"

New, Maria. "Role of HR23B, HDAC6 and Myd88 and their interplay in response to HDAC inhibitor treatment." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:096a4afc-98fa-41d5-b163-9287984cb1fa.

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Abnormal epigenetic control is a common early event in tumour progression, and aberrant acetylation in particular has been implicated in tumourigenesis. Histone deacetylases (HDACs) are enzymes that regulate acetylation of chromatin and a variety of other non-histone substrates. Significantly, HDAC inhibitors are potent anti-proliferative agents and exhibit clinical activity in lymphoproliferative and haematological maligancy. However, the mechanistic details by which HDAC inhibitors affect proliferation remain to be elucidated. I have explored the cellular processes affected by HDAC inhibitors, and begun to illuminate a new pathway, regulated by HDAC, which impinges on the cellular effect of HDAC inhibitors. My results suggest that the proteins HR23B and Myd88 are important sensitivity determinants for HDAC inhibitor treatment, and that their interplay with HDAC6 dictates cell fate choice between survival by autophagy or apoptosis.

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Landucci, Elisa. "Modeling Rett syndrome with iPSCs-derived neurons." Doctoral thesis, Università di Siena, 2018. http://hdl.handle.net/11365/1051069.

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Rett syndrome is a severe neurodevelopmental disorder. The condition affects approximately one in every 10.000 females and is only rarely seen in males. Causative mutations in the transcriptional regulator MeCP2 have been identified in more than 95% of classic Rett patients; mutations in CDKL5 are responsible for the early onset seizures Rett variant and mutations in FOXG1 gene lead to the congenital Rett variant. To shed light on molecular mechanisms underlying Rett syndrome onset and progression in disease-relevant cells, we took advantage of the breakthrough genetic reprogramming technology and we investigated changes in iPSC-derived neurons from patients with different MECP2 and FOXG1 mutations and in the brain of Foxg1+/- mice. In total brains from Foxg1+/ − mutants we noticed a statistically significant overexpression of a group of neuropeptides expressed in the basal ganglia, cortex, hippocampus and hypothalamus: Oxytocin (Oxt), Arginine vasopressin (Avp) and Neuronatin (Nnat).Moreover, in iPSC-derived neuronal precursors and neurons mutated in FOXG1 and in Foxg1+/− mouse embryonic brain (E11.5) compared to wild type controls we found an increase in the expression of GluD1 and inhibitory synaptic markers, such as GAD67 and GABA AR-α1 and a decreased expression of excitatory synaptic markers, such as VGLUT1, GluA1, GluN1 and PSD-95, suggesting an excitation/inhibition imbalance in the developing brain of the congenital RTT variant. Furthermore, we investigated transcriptome changes in neurons differentiated from MECP2 mutated iPSC-derived neurons and we noticed a prominent GABAergic circuit disruption and a perturbation of cytoskeleton dynamics. In particular, in MECP2-mutated neurons we identified a significant decrease of acetylated α-tubulin which can be reverted by treatment with a selective inhibitor of HDAC6, the main α-tubulin deacetylase. Taken togheter, these findings contribute to shed light on Rett pathogenic mechanisms and provide hints for the definition of new therapeutic strategies for Rett syndrome.

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Castaneda, Adrian Lance. "Selective histone deacetlyase inhibition decreases disease in lupus-prone mice." Thesis, Virginia Tech, 2016. http://hdl.handle.net/10919/72952.

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Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that acetylates several proteins that are involved in the immune response. HDAC6 inhibition has been shown in various models to decrease inflammation by altering various proteins involved in the dysregulation of B and T cell responses. In our current studies we sought to determine if HDAC6 inhibition would decrease disease in lupus-prone mice using two murine mouse models of SLE: MRL/lpr mice and NZB/W F1 mice. Both mouse models were fed a rodent diet formulated with the selective HDAC6 inhibitor ACY-738 (N-hydroxy-2-(1-phenylcycloproylamino) pyrimidine-5-carboxamide). NZBW mice received 18 weeks of treatment starting at 16-weeks-of-age and had an average of 57.3 +/- 14.6 ng/mL of ACY-738 in the plasma. MRL/lpr mice received 7 weeks of treatment starting at 11-weeks-of-age and had an average of 78.5 +/- 17.3 ng/mL of ACY-738 in the plasma. Controls received either dexamethasone 5x a week or were left untreated. As the mice aged, body weight, urine protein, and blood sera was collected weekly. Spleen cells were isolated following euthanasia for flow cytometry and kidneys were also collected for histological analyses. We found that in both mouse models that mice treated with ACY-738 had reduced splenic weight and IgG immunoglobulin isotypes. MRL/lpr mice that were treated with ACY-738 had a reduction in the number of IL-17+, ROR-gamma-t TH17 cells. NZBW/ F1 mice that received ACY-738 treatment also had a reduction in the TH17 cells and we observed a significant reduction in kidney pathology. Selective HDAC6 targeting may warrant future investigations as a potential therapeutic target for the treatment of SLE.
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Vieson, Miranda Diane. "Selective HDAC6 Inhibition in Systemic Lupus Erythematosus." Diss., Virginia Tech, 2017. http://hdl.handle.net/10919/74872.

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Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by abnormalities in multiple components of the immune system resulting in progressive damage to multiple organs. Current treatments for SLE are often intensive and result in side effects and the potential for continued flares and progression of disease. Histone deacetylase (HDAC) enzymes control multiple cellular functions by removing acetyl groups from lysine residues in various proteins. HDAC inhibitors have been investigated as a potential treatment for SLE with promising results, however selective HDAC6 inhibition (HDAC6i) has become a leading candidate for pharmacologic inhibition to reduce the potential for side effects. We hypothesize that HDAC6i will decrease SLE disease by targeting substrates of HDAC6 in multiple components of immunity and organ systems. NZB/W mice were treated with ACY-738 or ACY-1083, followed by evaluation of multiple disease parameters and mechanisms involved in disease pathogenesis within the kidney, bone marrow, and spleen. Within the kidney, HDAC6i decreased glomerular pathology scores, proteinuria, and IgG and C3 deposition. Within glomerular cells, HDAC6i increased alpha-tubulin acetylation and decreased nuclear NF-κB. Within the spleen, there was a dose-dependent decrease in the frequency of Th17 cells and a mild decrease in the frequency of Treg cells. Concurrently, there were decreased levels of IL-12/IL-23 and minimal decreases in TGF-β in the serum. Within the bone marrow, B cell development through Hardy fractions exhibited accelerated progression through later stages as NZB/W mice aged. This accelerated progression may allow B cells to bypass important regulatory checkpoints in maintaining immune tolerance and contribute to autoimmunity. Treatment with an HDAC6i corrected the aberrant B cell development in the bone marrow and RNAseq analysis unveiled six genes (Cebpb, Ccr9, Spib, Nfil3, Lgals1, and Pou2af1) that may play a role in the aforementioned abnormalities. Overall, these findings show that HDAC6i decreased disease in NZB/W mice by targeting multiple components of the immune response, including glomerular cells, T cell subsets in the spleen, and bone marrow B cells. In conclusion, selective HDAC6i is an excellent candidate for pharmacologic therapy for SLE because it targets multiple immune abnormalities involved in SLE pathogenesis while remaining selective and safe.
Ph. D.

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Losson, Hélène. "Combinaisons de nouveaux inhibiteurs de désacétylase d’histones 6 avec des inhibiteurs de tyrosine kinase pour le traitement de la leucémie myéloïde chronique." Thesis, Université de Lorraine, 2020. http://www.theses.fr/2020LORR0003.

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Les patients atteints de leucémie myéloïde chronique (LMC) breakpoint cluster region-Abelson (BCR-ABL)+ sont traités avec des inhibiteurs de tyrosine kinase (ITK), comme l’imatinib, cependant certains développent des résistances et des effets secondaires sévères. Des traitements combinés à base d’inhibiteurs d’histone désacétylase (HDAC)6 (HDAC6i), pouvant potentiellement réduire l’expression de BCR-ABL, apparaît être une approche intéressante pour prévenir l’apparition de résistances aux ITK. De plus, l’implication d’HDAC6 dans les voies de dégradation des protéines rend son inhibition couplée à celle du protéasome susceptible de sensibiliser les cellules aux ITK. Notre hypothèse est que la combinaison ITK-HDAC6i pourrait être efficace pour le traitement de la LMC. Dans un premier temps, les effets anti-cancéreux d’un HDAC6i identifié dans notre laboratoire, le composé 7b, à celui de référence, la tubacine, en combinaison avec l’imatinib ont été comparés. La combinaison imatinib-7b a généré des effets anti- cancéreux plus importants que la combinaison imatinib-tubacine et a provoqué une mort synergique apoptotique dépendante des caspases dans les cellules K-562 et réduit la proportion de cellules souches leucémiques alors qu’elle n’a eu qu’un effet modéré sur des cellules saines. Enfin, la combinaison a diminué plus fortement la capacité de formation de colonies et la masse tumorale des cellules de LMC respectivement en milieu semi-solide et dans des poissons zèbres xénogreffés, par rapport aux composés seuls. D’un point de vue mécanistique, la combinaison induit l’ubiquitination et la dégradation de BCR-ABL, et la dérégulation de protéines de ses voies de signalisation impliquées dans la prolifération et la survie cellulaire. La protéine HDAC6 possédant deux sites catalytiques, nos résultats tendent à montrer que le composé 7b cible le deuxième. Dans un second temps, une étude a été initiée sur un nouvel HDAC6i de type hydroxamate, le MAKV-15, qui diminue l’expression de BCR-ABL, et qui en pré-traitement avec le bortezomib, sensibilise les cellules à l’imatinib, entrainant une augmentation de la mort apoptotique dépendante des caspases dans les cellules sensibles et résistantes à l’imatinib. Enfin, nos résultats suggèrent que l’inhibition d’HDAC6 potentialise l’effet de l’imatinib, pourrait prévenir l’apparition de résistances et que de telles combinaisons pourraient représenter une approche thérapeutique prometteuse pour les patients atteints de LMC
Breakpoint cluster region-Abelson (BCR-ABL)+ chronic myeloid leukemia (CML) patients receive tyrosine kinase inhibitors (TKIs) such as imatinib as the first-line treatment; however, some patients develop resistances and severe adverse effects. Combination treatments, especially with histone deacetylase (HDAC)6 inhibitors (HDAC6i), appear as an attractive option to prevent TKI resistances considering the capacity of HDAC6i to downregulate BCR-ABL. Moreover, HDAC6 is implicated in protein degradation pathways, so that its inhibition combined with that of the proteasome could sensitize cells to TKIs. Thus, we hypothesized that HDAC6i combined to TKIs could be effective for CML treatment. In the first part, we compared the anti-CML effects of a HDAC6i identified in our laboratory, compound 7b, to the reference HDAC6i tubacin, in combination with imatinib. Results showed that the imatinib-7b combination generated stronger anti- CML effects than imatinib-tubacin. Especially, the imatinib-7b combination elicited a potent synergistic caspase- dependent apoptotic cell death and drastically reduced the proportion of cancer stem cells in K562 CML cells, whereas it only moderately impacted various healthy cell models. Ultimately, the imatinib-7b combination decreased more potently the colony forming capacities and tumor mass formation of CML cells in a semisolid methylcellulose medium and in xenografted zebrafishes, respectively, compared to each compound alone. Mechanistically, the combination induced BCR-ABL ubiquitination and downregulation leading to a dysregulation of multiple key proteins of its downstream pathways involved in CML proliferation and survival. Results tend to demonstrate that 7b could target the second site. In the second part, we initiated a study of a novel hydroxamate-based HDAC6i, MAKV-15, and preliminary results demonstrated it triggered BCR-ABL downregulation. Accordingly, in pre-treatment with bortezomib it sensitizes CML cells to imatinib leading to enhanced caspase-dependent apoptotic death in imatinib-sensitive and imatinib-resistant CML cells. Considering that HDAC6 is reported to possess two functional catalytic sites, we finally attempted to determine which catalytic site is targeted by these HDAC6i. Taken together, our results suggest that HDAC6i potentiate the effect of imatinib and could overcome TKI resistance in CML cells and therefore such combination may represent a promising therapeutic approach for CML patients

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Ozdarska, Katarzyna. "Synthèses d’inhibiteurs de HDAC et leurs tests biologiques (Cytotoxicité, HDAC inhibition)." Thesis, Reims, 2020. http://www.theses.fr/2020REIMS023.

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L’épigénétique représente les modifications de l’expression génique, sans altérer la séquence nucléique de l'ADN. L'un des mécanismes de régulation est le remodelage de la chromatine qui s’effectue via les histones acétyltransférases et les histones désacétylases (HDAC) permettant ou non la transcription de gènes. Une expression anormale des HDAC est corrélée à de nombreuses maladies (dépendance à l'alcool, inflammation ainsi que les maladies cardiovasculaires et neurodégénératives, cancers…). Il est primordial de cibler la sélectivité d’une isoforme parmi les 11 connues des HDAC zinc dépendantes pour éviter les effets secondaires. Le but de la recherche était de concevoir et de synthétiser de nouveaux composés, de vérifier leur activité inhibitrice vis-à-vis des HDAC de classe I ou II et leur cytotoxicité sur quatre lignées cellulaires: HaCaT, V79-4, SH-SY5Y et PC12. Ainsi, nous nous sommes concentrés sur les pharmacomodulations du ZBG, de l’espaceur et de la tête de molécules connues tels que le MS-275 (sélectif de la classe I des HDAC), les SAHA et TSA (espaceur en C5 ou C6) avec une forte activité inhibitrice vis-à-vis des HDAC, mais non sélectifs. Nous nous sommes concentrés sur les pharmacomodulations de l'HDACI connu modifiant le domaine de liaison au zinc ZBG (sulfonylhydrazide, catéchol), la nature de l’espaceur (alkyl, aryl) et le groupe de reconnaissance de surface (bis-aryl, adamantyl, indolopyridazinone). Une bibliothèque de 57 nouveaux composés a été créée en trois séries. Aucun d'entre eux n'a montré d'activité inhibitrice satisfaisante. Les composés sélectionnés n'ont pas montré d'activité cytotoxique sur les lignées de cellules neuronales. Sur la base de cette recherche, il est possible de créer de nouveaux composés dans la série indolopyridazinone afin de les tester
Epigenetics represents changes in gene expression without altering the nucleic sequence of DNA. One of the main mechanisms of regulation of gene expression is chromatin remodeling via histone acetyltransferases and histone deacetylases (HDAC), which may or may not allow gene transcription. An abnormal expression of HDACs is correlated with many diseases (alcohol dependence, inflammation as well as cardiovascular and neurodegenerative diseases, cancers...). It is essential to target the selectivity of one isoform among the 11 known zinc-dependent HDACs to avoid side effects. The aim of the research was to design and synthesize new compounds, verify their inhibitory activity against class I or II HDACs and their cytotoxicity on four cell lines: HaCaT, V79-4, SH-SY5Y and PC12. We focused on the pharmacomodulations of ZBG, the linker and the cap of known molecules such as MS-275 (selective for class I of HDACs), SAHA and TSA (spacer in C5 or C6) with a strong inhibitory activity towards HDACs, but not selective. We concentrated on the pharmacomodulations of known HDACI modifying the zinc binding domain (sulfonylhydrazide, catechol), the nature of the spacer (alkyl, aryl) and the surface recognition group (bis-aryl, adamantyl, indolopyridazinone). A library of 57 new compounds was designed in three series. None of them showed satisfactory inhibitory activity. The selected compounds did not show cytotoxic activity on neuronal cell lines. Based on this research, it is possible to create new compounds in the indolopyridazinone series in order to test them

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Leteve, Mathieu. "EPIADDICT - Synthèses de nouveaux inhibiteurs des histones désacétylases et leur intérêt dans un modèle préclinique d’addiction à l’alcool." Thesis, Reims, 2016. http://www.theses.fr/2016REIMS026/document.

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Le déséquilibre HAT/HDAC aurait une influence sur le développement de certains cancers ainsi que dans l’addiction à l’alcool ou à la cocaïne. En inhibant les histones désacétylases, le taux d'acétylation de la chromatine augmente ce qui permet l’accès aux facteurs de transcription et l'expression des gènes. Aujourd'hui, il existe de nombreux inhibiteurs d'HDAC de structures diverses, mais ils ne sont pas spécifiques et présentent des effets secondaires importants. Les inhibiteurs d'HDAC comme le butyrate de sodium ou le MS-275 ont montré une modification de la dépendance à l'alcool chez le rat. MS-275 inhibe principalement la classe I de HDAC et conformément à ces observations nous nous intéressons aux inhibiteurs les plus sélectifs de la classe I tels que le Largazole thiol et le RedFK228. Notre but est de synthétiser de nouveaux cyclodepsipeptides analogues afin d'obtenir un inhibiteur sélectif de la classe I. Les HDAC de la classe I sont Zn-dépendants, ces analogues auront un groupement sulfonylhydrazide ayant une bonne affinité pour l’ion Zn2+ (ZBG). Il sera relié au cyclodepsipeptide par un bras espaceur dont la longueur sera adaptée (n = 2, 3). Une autre pharmacomodulation concerne l'incorporation d’hétérocycles différents (oxazole, thiazole et pyridine). Les inhibitions de ces composés ont pu être testées sur HDAC1, HDAC3 et HDAC6. Un composé a une spécificité pour HDAC3 et un autre a une spécificité pour HDAC1. Les tests sur des rats "binger" permettent de penser que HDAC1 est impliqué dans ce model de consommation et non HDAC3
The imbalance HAT/HDAC would influence the development of cancers and alcohol or cocaine addiction. HDAC inhibition allows increase of both acetylation rate and gene expression. Today, there are many structurally diverse potent, but non-specific HDAC inhibitors displaying important side-effects. HDAC inhibitors such as sodium butyrate or MS-275 have been shown to alter the alcohol dependence in the rat. MS-275 inhibits mainly class I of HDAC and in line with these observations we are interested in more selective class I inhibitors such as Largazole thiol and RedFK228. Our purpose is to synthesize new cyclodepsipeptides analogues in order to obtain selective class I inhibitor. HDAC class I is a Zn-dependent enzyme and our target molecules have sulfonylhydrazide function as efficient Zinc binding group (ZBG). Additional pharmacomodulations concern the incorporation of different heterocycles (oxazole, thiazole, pyridine) and varying linker lengths (n = 2, 3). Inhibitions of these compounds have been tested on HDAC1, HDAC3 and HDAC6. A compound has specificity for HDAC3 and another has specificity for HDAC1. Tests on rats "binger" suggest that HDAC1 is involved in this model of consumption and not HDAC3

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Lu, Qiang. "Potent short-chain fatty acid-based histone deacetylase inhibitors as anti-tumor agents." Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1117541292.

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Thesis (Ph. D.)--Ohio State University, 2005.
Title from first page of PDF file. Document formatted into pages; contains xix, 116 p.; also includes graphics. Includes bibliographical references (p. 106-116). Available online via OhioLINK's ETD Center

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Sodre, De Castro Laino Andressa. "Targeting Histone Deacetylases in Melanoma and T-cells to Improve Cancer Immunotherapy." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6144.

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Histone deacetylases (HDACs) are key mediators of gene expression and, thus, major regulators of cell function. As such, HDACs play a role in orchestrating tumor biology, and the use of small inhibitors targeting theses proteins is attractive for the field of cancer therapy. Indeed, several HDAC inhibitors have received FDA-approval for the treatment of malignancies, while a myriad of these compounds continue to be evaluated in clinical trials. Besides their direct impact on tumor growth, HDAC inhibitors have been shown to increase immunogenicity of cancer cells, facilitating generation of a productive immune response against tumors. Immunotherapeutic approaches take advantage of the intrinsic ability of the immune system to manifest an anti-tumor response. Mechanisms of immune escape are often developed by cancer cells, neutralizing activity of the immune system. For example, upregulation of the PD1 ligands PDL1 and PDL2 by tumor cells negatively regulates the anti-tumor functions of PD1-expressing infiltrating T-cells. Importantly, strategies targeting this inhibitory axis have shown outstanding clinical benefit for the treatment of solid and hematological malignancies. The mechanisms by which HDAC inhibitors modulate tumor and immune cells biology were explored herein. Initially, treatment of melanoma cells with pan- and class I-selective HDAC inhibitors resulted in upregulation of PDL1 and PDL2 molecules. These effects were observed in mouse and human cell lines, as well as in tumor cells resected from metastatic melanoma patients. This upregulation was robust and sustained, lasting at least 96 hours in vitro, and validated in vivo using a B16F10 syngeneic mouse model. Enhanced expression of PDL1 mediated by HDAC inhibitors was found to result from enhanced histone acetylation at the PDL1 gene promoter region. Combination therapy of HDAC inhibition and PD1 blockade was explored in the tumor setting, leading to synergistic effects in terms of reducing melanoma progression and increasing survival of B16F10 melanoma-bearing mice. These data provide a clinical rationale for combination therapy of epigenetic modifiers (e.g. HDAC inhibitors) and PD1 blockade as means to augment cancer immunotherapy, improving patient outcomes. As a second pillar of this research, the impacts of HDAC-selective inhibition were explored on immune cell biology, since the broad nature of pan-HDAC inhibitors was shown to be detrimental to T-cells in vitro and in vivo. Based on screening assay results, novel implications of treating melanoma patient T-cells ex vivo with the HDAC6-selective inhibitor ACY1215 were investigated. Treatment with this compound was unique among pan- and isotype-selective HDAC inhibitors in modulating T-cell cytokine production and showing minimal impact of T-cell viability. ACY1215 tempered Th2 cytokine production (i.e. IL-4, IL-6 and IL-10), and maintained Th1 effector cytokines (e.g. IFNγ and IL-2). Furthermore, ACY1215 increased expression of surface markers, including CD69 activation marker and ICOS co-stimulatory molecule. In addition, ACY1215 treatment enhanced accumulation of central memory T-cells during ex vivo expansion of tumor infiltrating T-cells harvested from resected tumors of metastatic melanoma patients. Importantly, ACY1215-mediated inhibition improved tumor-killing capacity of T-cells. These results highlight an unexplored ability of selective HDAC inhibitor ACY1215 to augment T-cell expansion during protocols of adoptive cell therapy. While the discoveries presented here warrant further investigation of cellular and molecular mechanisms associated with ACY1215-treated T-cells, the clinic implications are clear and rapidly translatable.

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Khan, Omar Ali. "HR23B, a biomarker for HDAC inhibitors." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:9cd76c0b-e70e-43f7-a92d-a99f403a077e.

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As our understanding of cancer biology increases and novel therapies are developed, an increasing number of predictive biomarkers are becoming clinically available. Aberrant acetylation has been strongly linked to tumourigenesis and the modulation of acetylation through targeting histone deacetylase (HDAC) has led to the introduction of many HDAC inhibitors. To date, two have had regulatory approval for the treatment of cutaneous T cell lymphoma (CTCL). Modifications in chromatin control underpin the mechanism of action of HDAC inhibitors. A genome wide loss-of-function screen identified HR23B as a gene that governs sensitivity to HDAC inhibitors. HR23B shuttles ubiquitinated cargo proteins to the proteasome and elevated levels may contribute to cell death mediated by this pathway. It also governs cell sensitivity to drugs that act directly on the proteasome. HDAC inhibitors influence proteasome activity and there may be a synergistic interaction with proteasome inhibitors. HR23B and HDAC6 interact and HDAC6 may be a negative regulator of apoptosis and a positive regulator of autophagy and through its ability to down-regulate HR23B, may impact on the cellular outcome of HDAC inhibitor treatment. Expression of HR23B has been correlated with clinical response to HDAC inhibitors in a retrospective analysis of CTCL patients. The tissue expression of HR23B and the autophagy marker LC3 has been investigated and there may be a reciprocal relationship in their expression in some tumours which may provide prognostic information and patients with low HR23B expression but high levels of autophagy appear to have a particularly poor prognosis. Well designed, biomarker-driven prospective clinical trials are needed to clarify the predictive and prognostic roles of HR23B.

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Книги з теми "Inhibitor of HDAC6"

Krämer, Oliver H., ed. HDAC/HAT Function Assessment and Inhibitor Development. New York, NY: Springer US, 2023. http://dx.doi.org/10.1007/978-1-0716-2788-4.

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Krämer, Oliver H., ed. HDAC/HAT Function Assessment and Inhibitor Development. New York, NY: Springer New York, 2017. http://dx.doi.org/10.1007/978-1-4939-6527-4.

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Hodgkiss, Andrew. Psychiatric consequences of cancer treatments: ‘small molecule’ molecularly targeted agents. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780198759911.003.0008.

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The psychiatric consequences of a range of small-molecule, molecularly targeted systemic treatments for cancer are reviewed. Psychopathology may arise from the endocrine complications of VEGFR/multiple TK inhibitors. The mechanisms by which PI3K/AKT inhibition and proteasome inhibition can provoke anxiety and depressive phenomena in animals and humans are discussed. PARP-1 inhibition impairs memory acquisition in animal models and is neuroprotective. PARP-2 inhibitors display anti-neuroinflammatory properties in mice. The cognitive enhancing, mood stabilizing, and neuroprotective effects of HDAC inhibitors are considered.

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Edara, Anna Purna. Fighting Cancer Through HDAC and MAPK Inhibitors. Independently Published, 2013.

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Hdac/Hat Function Assessment and Inhibitor Development: Methods and Protocols. Springer New York, 2016.

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Krämer, Oliver H. HDAC/HAT Function Assessment and Inhibitor Development: Methods and Protocols. Springer New York, 2018.

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Krämer, Oliver H. HDAC/HAT Function Assessment and Inhibitor Development: Methods and Protocols. Springer, 2022.

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Ganai, Shabir Ahmad. Natural HDAC Inhibitors for Epigenetic Combating of Cancer Progression. Taylor & Francis Group, 2023.

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Natural Hdac Inhibitors for Epigenetic Combating of Cancer Progression. CRC Press LLC, 2023.

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Ganai, Shabir Ahmad. Natural HDAC Inhibitors for Epigenetic Combating of Cancer Progression. Taylor & Francis Group, 2023.

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Частини книг з теми "Inhibitor of HDAC6"

Bloch, Michael H., Michael H. Bloch, Mark A. Geyer, David C. S. Roberts, Eileen M. Joyce, Jonathan P. Roiser, John H. Halpern, et al. "HDACs Inhibitors." In Encyclopedia of Psychopharmacology, 577. Berlin, Heidelberg: Springer Berlin Heidelberg, 2010. http://dx.doi.org/10.1007/978-3-540-68706-1_3299.

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Schwab, Manfred. "HDAC Inhibitors." In Encyclopedia of Cancer, 1. Berlin, Heidelberg: Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-642-27841-9_2591-2.

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Olzscha, Heidi, Mina E. Bekheet, Semira Sheikh, and Nicholas B. La Thangue. "HDAC Inhibitors." In Methods in Molecular Biology, 281–303. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4939-3667-0_19.

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Ito, Akihiro, Norikazu Nishino, and Minoru Yoshida. "HDAC Inhibitors." In Histone Deacetylases, 271–97. Totowa, NJ: Humana Press, 2006. http://dx.doi.org/10.1385/1-59745-024-3:271.

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Kwon, Paul, Meier Hsu, Dalia Cohen, and Peter Atadja. "HDAC Inhibitors." In Histone Deacetylases, 315–32. Totowa, NJ: Humana Press, 2006. http://dx.doi.org/10.1385/1-59745-024-3:315.

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Ganai, Shabir Ahmad. "HDACs and Their Distinct Classes." In Histone Deacetylase Inhibitors — Epidrugs for Neurological Disorders, 21–25. Singapore: Springer Singapore, 2019. http://dx.doi.org/10.1007/978-981-13-8019-8_3.

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Atadja, Peter W. "HDAC Inhibitors and Cancer Therapy." In Epigenetics and Disease, 175–95. Basel: Springer Basel, 2010. http://dx.doi.org/10.1007/978-3-7643-8989-5_9.

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Ruzic, Dusan, Nemanja Djokovic, and Katarina Nikolic. "Fragment-Based Drug Design of Selective HDAC6 Inhibitors." In Methods in Molecular Biology, 155–70. New York, NY: Springer US, 2021. http://dx.doi.org/10.1007/978-1-0716-1209-5_9.

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Ganai, Shabir Ahmad. "Implications of HDACs in Neurological Disorders." In Histone Deacetylase Inhibitors — Epidrugs for Neurological Disorders, 27–31. Singapore: Springer Singapore, 2019. http://dx.doi.org/10.1007/978-981-13-8019-8_4.

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Shankar, Sharmila, and Rakesh K. Srivastava. "Histone Deacetylase Inhibitors: Mechanisms and Clinical Significance in Cancer: HDAC Inhibitor-Induced Apoptosis." In Advances in Experimental Medicine and Biology, 261–98. Dordrecht: Springer Netherlands, 2008. http://dx.doi.org/10.1007/978-1-4020-6554-5_13.

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Тези доповідей конференцій з теми "Inhibitor of HDAC6"

Grindrod, Scott, Satish Noonepalle, Nima Aghdam, Alfredo Velena, Maria Gracia-Hernandez, Christian Zevallos-Delgado, Mira Jung, Anatoly Dritschilo, and Alejandro Villagra. "Abstract PO023: Immune-mediated tumor growth inhibition by selective HDAC6 inhibitor SP-2-225." In Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; October 19-20, 2020. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/2326-6074.tumimm20-po023.

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Knox, Tessa, Eva Sahakian, Debarati Banik, Melissa Hadley, Erica Palmer, Jennifer Kim, John Powers, et al. "Abstract 1703: The HDAC6 inhibitor Nexturastat A improvesin vivoPD-1 immune blockade." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-1703.

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Pan, Qingfei, Tizita Zeleke, Cody Chiuzan, Maika Onishi, Mariano Alvarez, Erin Honan, Min Yang, et al. "Abstract 645: Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-645.

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Hadley, Melissa, Sida Shen, Debarati Banik, Jennifer Kim, Jayakumar Nair, Tessa Knox, Vincent Gallub, et al. "Abstract LB-294:In vivoevaluation of Ames negative HDAC6 inhibitor in melanoma model." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-lb-294.

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Sivanandhan, Dhanalakshmi, Sridharan Rajagopal, Sreekala Nair, Basavaprabhu B, Reshma Dhkar, Santosh Viswakarma, Amir Siddiqui, et al. "Abstract 1756: JBI-802, novel dual inhibitor of LSD1-HDAC6 for treatment of cancer." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-1756.

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Li, Zhenhu, Zhaoxiang Ren, Jingshu Ma, Liang Tang, Liang Lu, Ying Zhu, Yunfei Wu, et al. "Abstract 4441: CS3003, an HDAC6-selective inhibitor, improves anti-PD-1 immune checkpoint blockade therapy efficacy." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-4441.

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Kaliszczak, Maciej, Olivier E. Pardo, Michael J. Seckl, and Eric O. Aboagye. "Abstract A15: HDAC6 inhibitor C1A abrogates the recruitment of the autophagic machinery and synergizes with proteasome, src kinase, and PI3K-mTOR inhibition." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Oct 19-23, 2013; Boston, MA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1535-7163.targ-13-a15.

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Cheng, Fengdong, Sodre Andressa, Jie Chen, Alejandro Villagra, David Woods, Jeffrey Weber, Steven Quayle, Jones Simon, and Eduardo Sotomayor. "Abstract 4976: Ricolinostat, a selective HDAC6 inhibitor with immunomodulatory properties, has significant antimelanoma activity in vitro and in vivo." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-4976.

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Tsimberidou, Apostolia M., Philip Beer, Jennifer Bendall, James Dow, Justine King, Hilary McElwaine-Johnn, and Ignacio I. Wistuba. "Abstract CT151: Phase I study of KA2507, a selective HDAC6 inhibitor, in patients with relapsed or refractory solid tumors." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-ct151.

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Kelter, Gerhard, Thomas Metz, Stolfa Diana, Manfred Jung, and Heinz-Herbert Fiebig. "Abstract C186: In vitro profiling and compare analysis of the novel HDAC6-selective inhibitor ST80 in 42 human tumor cell lines." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1535-7163.targ-11-c186.

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Звіти організацій з теми "Inhibitor of HDAC6"

Ellis, Leigh. Inhibition of Histone Deacetylases (HDACs) and mTOR Signaling: Novel Strategies Towards the Treatment of Prostate Cancer. Fort Belvoir, VA: Defense Technical Information Center, April 2012. http://dx.doi.org/10.21236/ada562460.

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Chinnaiyan, Prakash, and Paul M. Harari. Enhancing the Anti-Tumor Activity of ErbB Blockers with Histone Deaccetylase (HDAC) Inhibition in Prostate Cancer Cell Lines. Fort Belvoir, VA: Defense Technical Information Center, November 2005. http://dx.doi.org/10.21236/ada458444.

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Chinnaiyan, Prakash, and Paul M. Harari. Enhancing the Anti-tumor Activity of ErbB Blockers with Histone Deaccetylase(HDAC)Inhibition in Prostate Cancer Cell Lines. Fort Belvoir, VA: Defense Technical Information Center, May 2007. http://dx.doi.org/10.21236/ada472066.

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HDAC6 screening dataset using tau-based substrate in an enzymatic assay yields selective inhibitors and activators. EMBL-EBI, August 2022. http://dx.doi.org/10.6019/chembl4808148.

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