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Zeitschriftenartikel zum Thema "YAP/TEAD COMPLEX"
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Pobbati, Ajaybabu V., und Brian P. Rubin. „Protein-Protein Interaction Disruptors of the YAP/TAZ-TEAD Transcriptional Complex“. Molecules 25, Nr. 24 (18.12.2020): 6001. http://dx.doi.org/10.3390/molecules25246001.
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The identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have shown that YAP/TAZ are no longer oncogenic when their interaction with the TEAD family of transcription factors is disrupted. The transcriptional co-regulator YAP (its homolog TAZ) interact with the surface pockets of TEADs. Peptidomimetic modalities like cystine-dense peptides and YAP cyclic and linear peptides exploit surface pockets (interface 2 and interface 3) on TEADs and function as PPIDs. The TEAD surface might pose a challenge for generating an effective small molecule PPID. Interestingly, TEADs also have a central pocket that is distinct from the surface pockets, and which small molecules leverage exclusively to disrupt the YAP/TAZ-TEAD interaction (allosteric PPIDs). Although small molecules that occupy the central pocket belong to diverse classes, they display certain common features. They are flexible, which allows them to adopt a palmitate-like conformation, and they have a predominant hydrophobic portion that contacts several hydrophobic residues and a small hydrophilic portion that faces the central pocket opening. Despite such progress, more selective PPIDs that also display favorable pharmacokinetic properties and show tolerable toxicity profiles are required to evaluate the feasibility of using these PPIDs for cancer therapy.
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Kim, Jisook, Seung Hyun Jung, Seon Yeong Han, Jihee Yoon, Minjeong Kim, Jooyun Byun, Heesun Moon et al. „Abstract 1614: Antitumor activity of novel and potent YAP/TAZ-TEAD inhibitorstargeting the Hippo pathway in solid tumors“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 1614. http://dx.doi.org/10.1158/1538-7445.am2023-1614.
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Abstract The Hippo pathway is evolutionarily conserved and known to regulate diverse cellular processes, including cell survival, proliferation, differentiation, migration, and organ size. The key regulator of Hippo pathway is transcriptional enhanced associate domain (TEAD) transcription factors, which directly bind with YAP/TAZ and then drive the multiple signaling by activating target gene expression on nuclear. Loss-of-function mutations in the upstream activators, NF2-LATS1/2-MST1/2, trigger YAP/TAZ nuclear translocation and target gene transcription (Hippo-off state). This YAP/TAZ-TEAD complex is overexpressed and leads to metastatic progression in various cancers including malignant mesothelioma, NSCLC, ovarian cancer or cholangiocarcinoma. A recent development in targeting the Hippo pathway has been focused on the discovery of a central lipophilic pocket in TEAD amenable to the small-molecule binding site of autopalmitoylation. Within this lipophilic palmitate pocket, post-translational S-palmitoylation of TEAD at a conserved catalytic cysteine (Cys) residue (e.g., C380) leads to TEAD stabilization and is believed to be critical for maintaining appropriate protein folding to enable the formation of the transcriptionally active YAP/TAZ -TEAD complex. Therefore, targeting the palmitate pocket with allosteric small molecules inhibitor disrupt the formation of the YAP/TAZ-TEAD complex and modulate YAP/TAZ-TEAD driven gene transcription. We have identified a series of novel, potent small-molecule inhibitors of the YAP/TAZ-TEAD transcriptional complex. It showed under 20 nM of potency in the inhibition of TEAD luciferase reporter assay in MCF7-TEAD-luc cells. These TEAD inhibitors inhibited YAP/TAZ-TEAD protein-protein interaction in H226 cells harboring neurofibromin 2 (NF2) alteration. In addition, our lead compounds exhibited dose-dependent growth inhibitory effects in Hippo pathway-altered cancer cell lines and reduced the YAP/TAZ-TEAD target gene expression, CTGF, and CYR61 in H226 cells. Our lead compounds, singled out and optimized based on in vitro functional assay, displayed favorable pharmacokinetic and safety profiles. Furthermore, orally administered lead compound effectively suppressed tumor growth within tolerable doses in xenograft mice with tumors harboring NF2 alteration as a major upstream molecule of the Hippo pathway. In summary, we pointed our novel YAP/TAZ-TEAD inhibitors that showed excellent efficacy in Hippo-altered mutant cancer in vitro and in vivo xenograft models. These data best support a therapeutic option for the treatment of cancers with amplified or overexpressed YAP, TAZ, or TEAD genes. Further preclinical studies will be performed and reported soon after the establishment of a preclinical candidate. Citation Format: Jisook Kim, Seung Hyun Jung, Seon Yeong Han, Jihee Yoon, Minjeong Kim, Jooyun Byun, Heesun Moon, Eunyoung Lee, Yu-Yon Kim, Hyunjin Park, So-Ye Jeon, Young Gil Ahn, Young Hoon Kim, Kwee Hyun Suh. Antitumor activity of novel and potent YAP/TAZ-TEAD inhibitorstargeting the Hippo pathway in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1614.
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Moure, Casey J., Christopher Sondey, Mangeng Cheng, My Mansueto, Rafael Fernandez, Sebastian E. Schneider, Julia V. Ramirez et al. „Abstract 3938: Discovery of a novel small molecule inhibitor of the YAP1/TAZ-TEAD transcriptional complex“. Cancer Research 82, Nr. 12_Supplement (15.06.2022): 3938. http://dx.doi.org/10.1158/1538-7445.am2022-3938.
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Abstract Hippo pathway alterations in human cancers often result in dephosphorylation of yes-associated protein (YAP1) and its paralog TAZ (WWTR1), allowing the formation of an active complex with transcriptional enhanced associate domain transcription factors (TEADs). This complex formation results in the activation of pro-survival and pro-proliferative transcriptional programs in cancer cells. Many tumor types harbor alterations in the Hippo pathway, including mesothelioma, where a high percentage of tumors are driven by YAP1/TEAD activity. Although traditionally difficult to drug with small molecules, identification of autopalmitoylation sites in the hydrophobic palmitate pocket of TEADs necessary for YAP1 interaction has enabled modern drug discovery platforms to generate compounds that allosterically inhibit YAP1/TAZ-TEAD complex formation and transcriptional activity. We report the discovery and characterization of the novel YAP1/TAZ-TEAD inhibitor MRK-A from an aryl ether chemical series demonstrating potent and specific inhibition of YAP1/TAZ-TEAD activity. In biochemical thermal shift assays, MRK-A caused a concentration-dependent melting temperature shift of 8-12.5 and 0.6-1.5 degrees for TEAD1 and TEAD2, respectively, indicating direct binding to TEAD protein. In cellular assays, MRK-A demonstrated inhibition of a TEAD-based reporter assay, with little to no activity in multiple orthogonal off-target reporter assays such as WNT, NF-KB, TGFB and PPARG (8.4 nM vs. >10000 nM), which is consistent with the exquisite selectivity profile of this molecule (>1000x selectivity against 350+ measured kinases and other common off-targets). In the NF2-deficient mesothelioma cell line H226, MRK-A suppressed the transcription of endogenous YAP/TAZ-TEAD target genes CYR61, ERBB3, ANKRD1 and CTGF (50-75% inhibition at 100 nM), but not LATS1, a non-TEAD regulated Hippo pathway gene. In co-immunoprecipitation assays, MRK-A disrupted the interaction of YAP1 and TEAD in H226 cells at concentrations consistent with inhibition of target genes. In addition, MRK-A potently blocked the clonogenic growth and viability of H226 cells in a dose-dependent manner (maximal response at 1 µM compound >90% growth inhibition), while sparing the Hippo wild-type mesothelioma cell line H28. Furthermore, structurally similar control compounds, MRK-B and MRK-C, without the ability to block TEAD-mediated transcription (TEAD reporter MCF7 assay IC50 > 10000 nM), did not impact the clonogenic growth of H226 cells. In vivo, MRK-A did not show acute tolerability signals in mice and demonstrated pharmacokinetics suitable for daily oral dosing in efficacy studies. In summary, we report the structure and characterization of MRK-A demonstrating potent and specific inhibition of YAP1/TAZ-TEAD mediated transcriptional responses, with potential implications for treating malignancies driven by altered Hippo signaling. Citation Format: Casey J. Moure, Christopher Sondey, Mangeng Cheng, My Mansueto, Rafael Fernandez, Sebastian E. Schneider, Julia V. Ramirez, Brian Long, Erin DiMauro, Brandon Vara, Charles Yeung, Abe Achab, Jongwon Lim, Ronald Kim, Cayetana Zarate, Jonathan Bennett, Rachel Palte, Robert Foti, Vladimir Simov, Evan Barry. Discovery of a novel small molecule inhibitor of the YAP1/TAZ-TEAD transcriptional complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3938.
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Li, Z., B. Zhao, P. Wang, F. Chen, Z. Dong, H. Yang, K. L. Guan und Y. Xu. „Structural insights into the YAP and TEAD complex“. Genes & Development 24, Nr. 3 (01.02.2010): 235–40. http://dx.doi.org/10.1101/gad.1865810.
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Lauriola, Angela, Elisa Uliassi, Matteo Santucci, Maria Laura Bolognesi, Marco Mor, Laura Scalvini, Gian Marco Elisi et al. „Identification of a Quinone Derivative as a YAP/TEAD Activity Modulator from a Repurposing Library“. Pharmaceutics 14, Nr. 2 (10.02.2022): 391. http://dx.doi.org/10.3390/pharmaceutics14020391.
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The transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) are the major downstream effectors in the Hippo pathway and are involved in cancer progression through modulation of the activity of TEAD (transcriptional enhanced associate domain) transcription factors. To exploit the advantages of drug repurposing in the search of new drugs, we developed a similar approach for the identification of new hits interfering with TEAD target gene expression. In our study, a 27-member in-house library was assembled, characterized, and screened for its cancer cell growth inhibition effect. In a secondary luciferase-based assay, only seven compounds confirmed their specific involvement in TEAD activity. IA5 bearing a p-quinoid structure reduced the cytoplasmic level of phosphorylated YAP and the YAP–TEAD complex transcriptional activity and reduced cancer cell growth. IA5 is a promising hit compound for TEAD activity modulator development.
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Sheldon, Caroline, Aaron Farley, Qing Ma, William T. Pu und Zhiqiang Lin. „Depletion of VGLL4 Causes Perinatal Lethality without Affecting Myocardial Development“. Cells 11, Nr. 18 (10.09.2022): 2832. http://dx.doi.org/10.3390/cells11182832.
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Congenital heart disease is one of the leading causes of pediatric morbidity and mortality, thus highlighting the importance of deciphering the molecular mechanisms that control heart development. As the terminal transcriptional effectors of the Hippo–YAP pathway, YAP and TEAD1 form a transcriptional complex that regulates the target gene expression and depletes either of these two genes in cardiomyocytes, thus resulting in cardiac hypoplasia. Vestigial-like 4 (VGLL4) is a transcriptional co-factor that interacts with TEAD and suppresses the YAP/TEAD complex by competing against YAP for TEAD binding. To understand the VGLL4 function in the heart, we generated two VGLL4 loss-of-function mouse lines: a germline Vgll4 depletion allele and a cardiomyocyte-specific Vgll4 depletion allele. The whole-body deletion of Vgll4 caused defective embryo development and perinatal lethality. The analysis of the embryos at day 16.5 revealed that Vgll4 knockout embryos had reduced body size, malformed tricuspid valves, and normal myocardium. Few whole-body Vgll4 knockout pups could survive up to 10 days, and none of them showed body weight gain. In contrast to the whole-body Vgll4 knockout mutants, cardiomyocyte-specific Vgll4 knockout mice had no noticeable heart growth defects and had normal heart function. In summary, our data suggest that VGLL4 is required for embryo development but dispensable for myocardial growth.
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Kim, Eui Hyun, und Seok-Gu Kang. „CSIG-25. DIFFERENTIAL YAP ACTIVITY IN HUMAN GLIOBLASTOMA TUMORSPHERES AS A POTENTIAL BIOMARKER“. Neuro-Oncology 24, Supplement_7 (01.11.2022): vii44. http://dx.doi.org/10.1093/neuonc/noac209.174.
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Abstract BACKGROUND Hippo/YAP signaling pathway has emerged as an important driver of GBM. However, the clinical significance and expression correlation of YAP in GBM is still unknown. The purpose of this study is to elucidate the regulatory functions of YAP in response to tumorspheres (TS) in GBM. Material and METHODS In GBM-tumorspheres (TS), mRNA levels of Yap1 and TAZ were determined by RNA-Seq, and nuclear YAP1 expression level and its correlation with tumor aggressiveness were assessed through nucleus cytosolic fractionation, quantitative confocal microscopy, western blot, and TEAD4 reporter assay. Cell proliferation, stemness, and invasive properties were also measured using YAP siRNA and its inhibitor Verteporfin to reveal the effect of YAP on glioma progression. In orthotopic xenograft models, the inhibition of YAP function were tested. RESULTS All GBM-TS exhibited various phosphorylation states of YAP but no significant differences regarding the expression of YAP. Among them, TS15-88 cell line showed relatively low YAP phosphorylation in the quantified immunoblot results. Indeed, TS with reduced YAP phosphorylation was associated with aggressive cancer phenotypes. Predominant nuclear localization of YAP and binding of YAP/TAZ to TEAD in the nucleus was evident in the TS15-88 cells. The YAP knockdown (KD) by siRNA significantly resulted decrease in TS proliferation through WST and ATP assay and values were validated again through YAP inhibitor, Verteporfin (VP). YAP KD attenuated not only the invasion and stemness of TS but also caused a reduction in tumor volume and prolonged the overall survival of mice. CONCLUSION We showed alteration of gene activities by YAP and nuclear localization of YAP/TAZ complex contributes to GBM progression. Moreover, thus tuning of Yap activity results a marked suppression in aggressive phenotypes of cancer. These associations emphasize that the YAP signaling network highly suggests new therapeutic opportunities in diagnosing and treating GBM.
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Kim, Cho-Long, Yu-Su Shin, Sue-Hee Choi, Seroc Oh, Kyeongseob Kim, Han-Sol Jeong und Jung-Soon Mo. „Extracts of Perilla frutescens var. Acuta (Odash.) Kudo Leaves Have Antitumor Effects on Breast Cancer Cells by Suppressing YAP Activity“. Evidence-Based Complementary and Alternative Medicine 2021 (15.02.2021): 1–13. http://dx.doi.org/10.1155/2021/5619761.
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Yes-associated protein (YAP)/WW domain-containing transcription factor (TAZ) is critical for cell proliferation, survival, and self-renewal. It has been shown to play a crucial oncogenic role in many different types of tumors. In this study, we investigated the antitumor effect of the extracts of Perilla frutescens var. acuta (Odash.) Kudo leaves (PLE) on Hippo-YAP/TAZ signaling. PLE induced the phosphorylation of YAP/TAZ, thereby inhibiting their activity. In addition, the treatment suppresses YAP/TAZ transcriptional activity via the dissociation of the YAP/TAZ-TEAD complex. To elucidate the molecular mechanism of PLE in the regulation of YAP activity, we treated WT and cell lines with gene knockout (KO) for Hippo pathway components with PLE. The inhibitory effects of PLE on YAP-TEAD target genes were significantly attenuated in LATS1/2 KO cells. Moreover, we found the antitumor effect of PLE on MDA-MB-231 and BT549, both of which are triple-negative breast cancer (TNBC) cell lines. PLE reduced the viability of TNBC cells in a dose-dependent manner and induced cell apoptosis. Further, PLE inhibited the migration ability in MDA-MB-231 cells. This ability was weakened in YAP and TEAD-activated clones suggesting that the inhibition of migration by PLE is mainly achieved by regulating YAP activity. Taken together, the results of this study indicate that PLE suppressed cell growth and increased the apoptosis of breast cancer (BC) cells via inactivation of YAP activity in a LATS1/2-dependent manner.
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de Andrade, Leonardo Guedes, Valério Marques Portela, Esdras Corrêa Dos Santos, Karine de Vargas Aires, Rogério Ferreira, Daniele Missio, Zigomar da Silva et al. „FSH Regulates YAP-TEAD Transcriptional Activity in Bovine Granulosa Cells to Allow the Future Dominant Follicle to Exert Its Augmented Estrogenic Capacity“. International Journal of Molecular Sciences 23, Nr. 22 (16.11.2022): 14160. http://dx.doi.org/10.3390/ijms232214160.
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The molecular mechanisms that drive the granulosa cells’ (GC) differentiation into a more estrogenic phenotype during follicular divergence and establishment of follicle dominance have not been completely elucidated. The main Hippo signaling effector, YAP, has, however, emerged as a potential key player to explain such complex processes. Studies using rat and bovine GC demonstrate that, in conditions where the expression of the classic YAP-TEAD target gene tissue growth factor (CTGF) is augmented, CYP19A1 expression and activity and, consequently, estradiol (E2) secretion are reduced. These findings led us to hypothesize that, during ovarian follicular divergence in cattle, FSH downregulates YAP-TEAD-dependent transcriptional activity in GC to allow the future dominant follicle to exert its augmented estrogenic capacity. To address this, we performed a series of experiments employing distinct bovine models. Our in vitro and ex vivo experiments indicated that indeed FSH downregulates, in a concentration-dependent manner, mRNA levels not only for CTGF but also for the other classic YAP-TEAD transcriptional target genes ANKRD1 and CYR61 by a mechanism that involves increased YAP phosphorylation. To better elucidate the functional importance of such FSH-induced YAP activity regulation, we then cultured GC in the presence of verteporfin (VP) or peptide 17 (P17), two pharmacological inhibitors known to interfere with YAP binding to TEADs. The results showed that both VP and P17 increased CYP19A1 basal mRNA levels in a concentration-dependent manner. Most interestingly, by using GC samples obtained in vivo from dominant vs. subordinate follicles, we found that mRNA levels for CTGF, CYR61, and ANKRD1 are higher in subordinate follicles following the follicular divergence. Taken together, our novel results demonstrate that YAP transcriptional activity is regulated in bovine granulosa cells to allow the increased estrogenic capacity of the selected dominant follicle.
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Cheng, Wen-Chih, Osnat Bohana-Kashtan, Sebastien Morisot, Nailing Zhang, Qian Chen, Duojia Pan und Curt I. Civin. „The YAP Transcriptional Co-Activator Is Not Required for Mouse Hematopoiesis, at Steady State or After 5FU Treatment.“ Blood 116, Nr. 21 (19.11.2010): 1592. http://dx.doi.org/10.1182/blood.v116.21.1592.1592.
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Abstract Abstract 1592 The Yes-associated protein (YAP) is a transcriptional co-activator that interacts with many transcription factors, including RUNX2, p73, ERBB4, PEBP2α, p53BP2, SMAD7 and the TEAD/TEF proteins. Recently, it has been established that YAP is the major downstream molecule of the evolutionarily conserved Hippo signaling pathway. First elucidated in Drosophila, the Hippo signaling pathway controls organ size by regulating apoptosis and proliferation. Beginning a kinase cascade, the MST1/MST2 kinases (fly ortholog: Hippo) cooperate with the WW domain-containing SAV1 (fly ortholog: Salvador) to phosphorylate and activate the LATS1/LATS2 kinases (fly ortholog: Warts). In turn, activated LATS1/LATS2 phosphorylate and inactivate YAP (fly ortholog: Yorkie). Inactivated YAP binds to 14-3-3 and is kept in the cytosol. In contrast, unphosphorylated YAP binds to TEAD family transcription factors (fly ortholog: Scalloped) and the complex transactivates genes including cell cycle regulators (e.g. cyclin) and cell death inhibitors (e.g. IAPs, inhibitor of apoptosis). Therefore, inactivation of MST or LATS kinase, or overexpression of YAP results in organ/tissue overgrowth characterized by excessive cell proliferation and diminished apoptosis in both fly and mammals. In two transgenic mouse models, overexpression of YAP1 in liver results in reversible increase in liver size due to increased proliferation and decreased cell death of hepatocytes. Several pieces of evidence suggest that YAP regulates stem cell self-renewal and differentiation. First, transcriptional profiling of mouse stem cells (hematopoietic, neuronal and embryonic) identified both YAP1 and TEAD2 as 2 of the only 14 transcription factors commonly expressed in all 3 types of stem cell. Second, in many adult human tissues (e.g. intestine, lung, pancreas), YAP1 is preferentially expressed in stem-progenitor cell compartments. Third, in mouse intestine and chick neural tubes, overexpression of YAP results in expansion of intestinal or neural stem-progenitor cells, as well as inhibition of progenitor cell differentiation in vivo. Finally, it has been shown that YAP expression decreases during mouse ES cell differentiation. Ectopic expression of YAP can maintain ES cell pluripotency and prevent differentiation both in vitro and in vivo. Given that YAP has a proven role in regulating stem-progenitor cells in multiple tissue and multiple organisms, we set out to investigate whether YAP also regulate hematopoetic stem-progenitors in mouse and human. In conditional YAP knockout mice with a specific deletion of YAP expression in the hematopoetic system, we found no abnormalities at steady state in hemtaopoietic lineages, as assessed by CBC (complete blood counts) or immunophenotypic analysis. In addition, the YAP-null hematopietic stem-progenitors (HSPCs) had no change in vitro hematopoietic colony-forming cells. Furthermore, 5-fluorouracil treatment did not reveal a significant difference in blood cell numbers or types, between wild type and YAP-null mice. Although these results in mice suggest that YAP appears not to be required in hematopoiesis, overexpression of YAP, which promotes stem-progenitor cell proliferation in other tissues, may still provide an excellent opportunity to drive HSPC expansion. Disclosures: No relevant conflicts of interest to declare.
Dissertationen zum Thema "YAP/TEAD COMPLEX"
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Gibault, Floriane. „Conception, synthèse et évaluation d’inhibiteurs du complexe protéique YAP-TEAD à visée anticancéreuse“. Thesis, Lille 1, 2017. http://www.theses.fr/2017LIL10097.
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La voie Hippo, découverte chez la Drosophile et conservée chez les mammifères, a été identifiée comme un élément essentiel dans le contrôle de la taille des organes. Cette cascade de kinases régule la phosphorylation de l’effecteur terminal YAP (ou de son paralogue TAZ), un coactivateur transcriptionnel reconnu comme oncogène. Sa fonction est médiée par sa translocation nucléaire et son interaction avec les facteurs de transcription TEAD, pour former le complexe YAP-TEAD qui active l’expression des gènes cibles responsable de la prolifération cellulaire et de la croissance des organes. La surexpression des protéines YAP/TAZ/TEAD dans de nombreux cancers perturbe l’équilibre de la voie Hippo et favorise la formation du complexe protéique causant une hyperprolifération et la propagation des cellules cancéreuses. Inhiber cette interaction protéine-protéine est une cible thérapeutique prometteuse pour concevoir de nouveaux anticancéreux. Dans cette optique, le laboratoire a considéré deux stratégies. La première consiste à cibler la protéine YAP en synthétisant des dipyrrines, représentant des fragments de la Vertéporfine dans le but de définir le motif minimal requis pour conserver l’activité biologique. Une seconde approche implique la synthèse de ligands de TEAD capable de se positionner au sein de l’interface 3. Basée sur des études de modélisation moléculaire, une famille avec un noyau central triazolique a été optimisée pour établir des relations structure-activité. Les molécules synthétisées sont actuellement en cours d’évaluation, grâce à la mise au point des tests biologiques et physicochimiques, et les premiers résultats ont permis d’identifier un composé prometteurThe Hippo pathway, firstly described in Drosophila and highly conserved in mammals, has been demonstrated to play a crucial role in the organ size control. This kinase cascade regulates the phosphorylation of the downstream effector YAP (or its paralogue TAZ), a transcriptional coactivator with oncogenic activity. Its function is mediated by its nuclear translocation and interaction with the transcriptional factor TEAD, to form YAP-TEAD complex which activates the genes expression in charge of cell proliferation triggering organ growth. Overexpression of YAP/TAZ/TEAD protein in several cancers disrupts the Hippo pathway balance and urges on YAP-TEAD complex formation causing excessive proliferation and cancer development. Inhibiting this protein-protein interaction is thus a promising therapeutic target for the design of new anti-cancer drugs. In this goal, the laboratory has considered two strategies. The first one consists in targeting the YAP protein by synthesizing dipyrrins, representing Verteporfin fragments to define the minimal requirement yielding the expected biological activity. A second approach involves synthesizing TEAD ligands able to fit in specific interface 3. Based on molecular modeling, a triazole scaffold family was optimized to establish structure-activity relationship. Thanks to the biological and binding tests development, synthesized molecules evaluation is still in progress and the present first results have already allowed identifying a promising compound
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SINGH, SIMRAN. „EXPLORING NATURAL COMPOUNDS TARGETING THE HIPPO PATHWAY FOR POTENTIAL TREATMENT OF MENINGIOMA“. Thesis, 2023. http://dspace.dtu.ac.in:8080/jspui/handle/repository/19944.
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Drug development which is a bit challenging and complex process that involves the
development, discovery, design, and assessment of potential therapeutic agents.
Meningioma, most common among the brain tumor which are generally asymptomatic in
nature is characterized by the NF2 gene loss. The current treatment options such as
resection and radiotherapy have limitations, with high rates of relapse or recurrence. The
lack of FDA-approved drugs specific to meningioma necessitates the exploration of
alternative approaches. Currently combination of FDA approved drug for other cancer
were given to patients but the side effects and failure rates were high. To battle
meningioma, natural substances are being researched as potential inhibitors of particular
pathways, such as the YAP/TEAD complex in the Hippo signaling pathway. YAP/TEAD
complex is responsible for uncontrolled cell progression in meningioma , by targeting
this complex we can make a drug or treatment of meningioma. In this study, molecular
docking was used to undertake in silico work and inhibition approach was used to find
naturally occurring molecules with comparable structures that might potentially interact
with the target receptor. out of 50 phytochemical,10 were selected on the basis of
bioavailability test and lead likeness The white mulberry Morus alba plant's bark
flavonoid, sanggenon N, was discovered to be the study's lead substance. Sanggenon N
may have lesser negative effects than synthetic medications because the Sanggenon
family of chemicals has demonstrated therapeutic potential. Another flavonoid called
isostaivan showed the second-highest binding affinity.. Further analysis confirmed that
Sanggenon N could act as an inhibitor of the 6UYC protein, which is the TEAD complex
in Homo sapiens, thereby inhibiting the YAP/TEAD complex. This inhibition can
potentially suppress cell proliferation and tumor growth in meningioma. It is crucial to
emphasize that these results are based on in silico work and that additional validation
through wet lab research is required.
Bücher zum Thema "YAP/TEAD COMPLEX"
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Cappuccio, Massimiliano L., Hrsg. Handbook of Embodied Cognition and Sport Psychology. The MIT Press, 2019. http://dx.doi.org/10.7551/mitpress/10764.001.0001.
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The first systematic collaboration between cognitive scientists and sports psychologists considers the mind–body relationship from the perspective of athletic skill and sports practice. This landmark work is the first systematic collaboration between cognitive scientists and sports psychologists that considers the mind–body relationship from the perspective of athletic skill and sports practice. With twenty-six chapters by leading researchers, the book connects and integrates findings from fields that range from philosophy of mind to sociology of sports. The chapters show not only that sports can tell scientists how the human mind works but also that the scientific study of the human mind can help athletes succeed. Sports psychology research has always focused on the themes, notions, and models of embodied cognition; embodied cognition, in turn, has found striking confirmation of its theoretical claims in the psychological accounts of sports performance and athletic skill. Athletic skill is a legitimate form of intelligence, involving cognitive faculties no less sophisticated and complex than those required by mathematical problem solving. After presenting the key concepts necessary for applying embodied cognition to sports psychology, the book discusses skill disruption (the tendency to “choke” under pressure); sensorimotor skill acquisition and how training correlates to the development of cognitive faculties; the intersubjective and social dimension of sports skills, seen in team sports; sports practice in cultural and societal contexts; the notion of “affordance” and its significance for ecological psychology and embodied cognition theory; and the mind's predictive capabilities, which enable anticipation, creativity, improvisation, and imagination in sports performance. ContributorsAna Maria Abreu, Kenneth Aggerholm, Salvatore Maria Aglioti, Jesús Ilundáin-Agurruza, Duarte Araújo, Jürgen Beckmann, Kath Bicknell, Geoffrey P. Bingham, Jens E. Birch, Gunnar Breivik, Noel E. Brick, Massimiliano L. Cappuccio, Thomas H. Carr, Alberto Cei, Anthony Chemero, Wayne Christensen, Lincoln J. Colling, Cassie Comley, Keith Davids, Matt Dicks, Caren Diehl, Karl Erickson, Anna Esposito, Pedro Tiago Esteves, Mirko Farina, Giolo Fele, Denis Francesconi, Shaun Gallagher, Gowrishankar Ganesh, Raúl Sánchez-García, Rob Gray, Denise M. Hill, Daniel D. Hutto, Tsuyoshi Ikegami, Geir Jordet, Adam Kiefer, Michael Kirchhoff, Kevin Krein, Kenneth Liberman, Tadhg E. MacIntyre, Nelson Mauro Maldonato, David L. Mann, Richard S. W. Masters, Patrick McGivern, Doris McIlwain, Michele Merritt, Christopher Mesagno, Vegard Fusche Moe, Barbara Gail Montero, Aidan P. Moran, David Moreau, Hiroki Nakamoto, Alberto Oliverio, David Papineau, Gert-Jan Pepping, Miriam Reiner, Ian Renshaw, Michael A. Riley, Zuzanna Rucinska, Lawrence Shapiro, Paula Silva, Shannon Spaulding, John Sutton, Phillip D. Tomporowski, John Toner, Andrew D. Wilson, Audrey Yap, Qin Zhu, Christopher Madan
Buchteile zum Thema "YAP/TEAD COMPLEX"
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Hsu, Wynne, Mong Li Lee und Junmei Wang. „Mining Spatio-Temporal Graph Patterns“. In Temporal and Spatio-Temporal Data Mining, 227–61. IGI Global, 2008. http://dx.doi.org/10.4018/978-1-59904-387-6.ch011.
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Data mining in graph databases has received much attention. We have witnessed many algorithms proposed for mining frequent graphs. Inokuchi, Washio, and Nishimura (2002) and Karpis and Kumar (1998) introduce the Apriori-like algorithms, AGM and FSG, to mine the complete set of frequent graphs. However, both algorithms are not scalable as they require multiple scans of databases and tend to generate many candidates during the mining process. Subsequently, Yan and Han (2002) and Nijssen and Kok (2004) propose depth-first graph mining approaches called gSpan and Gaston, respectively. These approaches are essentially memory-based and their efficiencies decrease dramatically if the graph database is too large to fit into the main memory.
Konferenzberichte zum Thema "YAP/TEAD COMPLEX"
1
Velazquez, Antonio, und R. Andrew Swartz. „Gyroscopic Effects of Horizontal Axis Wind Turbines Using Stochastic Aeroelasticity via Spinning Finite Elements“. In ASME 2012 Conference on Smart Materials, Adaptive Structures and Intelligent Systems. American Society of Mechanical Engineers, 2012. http://dx.doi.org/10.1115/smasis2012-8118.
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Horizontal axis wind turbine (HAWTs) structures, throughout the years, have presumed to be of relatively simple construction, but wind-induced aerodynamic vibrations, wind-field conditions, and power requirements tend to lead to the need for increasingly complicated designs. One phenomenon that requires special attention is the gyroscopic or Coriolis effect. In general, blades design codes are written to optimize for lightness and slenderness, but also to withstand excitations at high frequency. As a result, gyroscopic motion derives as a nonlinear dynamic condition in the out-of-plane direction that is difficult to characterize by means of the well-known vibrational theory that has been established for their design and analysis. The present study develops and presents a probabilistic analysis of the precession — gyroscopic — effects of a wind turbine model developed for tapered-swept cross-sections of nt degree with nonlinear variations of mass and geometry along the body of the blade. A dynamic orthogonal decoupling method is utilized to successfully perform the aeroelastic analysis by decoupling the damped-gyroscopic equations of motion, as a result of the addition of Rayleigh damping — symmetric proportional mass and stiffness — within the linear system in study. Results are valid for yaw-free rotor configurations by means of unknown and random (though bounded) yaw rates. Simultaneously, those results can easily be expanded for yaw-controlled mechanisms. The yaw-free assumption presents a higher risk of potential reliability expectations, given the stochastic impairment of the gyroscopic nature that is present for out-of-plane axis motions, requiring special attention at higher frequencies. This impairment becomes particularly troublesome for blade profiles with tapered-swept cross-section variations. This uncertainty can be minimized by incorporating a mathematical framework capable of characterizing properly the yaw action such that gyroscopic effects can be fully interpreted and diagnosed. In summary, the main goal is to decipher the complexity of gyroscopic patterns of flexible rotor blades with complex shape configurations, but also to provide substantial elements to successfully approach yaw-mechanics of tapered-swept rotor blades.
2
Durali, Mohammad, und Mohammad Mahdi Jalili. „Time Saving Simulation of Long Train Derailment“. In ASME 2008 International Mechanical Engineering Congress and Exposition. ASMEDC, 2008. http://dx.doi.org/10.1115/imece2008-66885.
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This article presents a new method in determining long train derailment. A new strategy for building train models with large number of wagons has been developed. Previous studies have shown that in a train model, some of the details in the model of the wagons neighboring the wagon under study play minor role in dynamic behavior of the spotted wagon. To reduce the size of the overall model, one would tend to eliminate some of the details of the complex neighboring model having minor effect on overall behavior and trade a small approximation in results for large saving in computation time. In this research this idea is used to develop a train model with one full detail wagon model linked in a train model with a large number of wagons having 3 degrees of freedom. The 3 degrees of freedom wagon models are considered to have yaw, lateral and longitudinal motions. The detailed wagon model has 48 degrees of freedom including nonlinear springs, dampers and friction on sliding surfaces. Nonlinear equations of motion for train were developed using Newton-Euler method. The model was then used to simulate train behavior in passing a bend or applying severe brakes at different speeds. The results show very good agreement with the results of models with full degrees of freedoms in all wagons. The computation time is tremendously decreased in the new method.
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Alexandre, Armando, Raffaello Antonutti, Theo Gentils, Laurent Mutricy und Pierre Weyne. „Simplified Aerodynamic Loading Model for Non-Production Conditions for Floating Wind Systems Design“. In ASME 2021 3rd International Offshore Wind Technical Conference. American Society of Mechanical Engineers, 2021. http://dx.doi.org/10.1115/iowtc2021-3516.
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Abstract Floating wind is now entering a commercial-stage, and there are a significant number of commercial projects in countries like France, Japan, UK and Portugal. A floating wind project is complex and has many interdependencies and interfaces. During all stages of the project several participants are expected to use a numerical model of the whole system and not only the part the participant has to design. Examples of this are the mooring and floater designer requiring a coupled model of the whole system including also the wind turbine, the operations team requiring a model of the system to plan towing and operations. All these stakeholders require a coupled model where the hydrodynamics, aerodynamics and structural physics of the system are captured with different levels of accuracy. In this paper, we will concentrate on a simplified model for the aerodynamic loading of the turbine in idling and standstill conditions that can be easily implemented in a simulation tool used for floater, mooring and marine operations studies. The method consists of using a subset of simulations at constant wind speed (ideally close to the wind speed required for the simulations) run on a detailed turbine model on a rigid tower and fixed foundation — normally run by the turbine designer. A proxy to the aerodynamic loads on the rotor and nacelle (RNA) is to take the horizontal yaw bearing loads. The process is then repeated for a range of nacelle yaw misalignments (for example every 15° for 360°). A look-up table with the horizontal yaw bearing load for the range of wind-rotor misalignments investigated is created. The simplified model of the aerodynamic loads on the RNA consists of a fixed blade (or wing) segment located at the hub, where aerodynamic drag and lift coefficients can be specified. Using the look-up tables created using the detailed turbine model, drag and lift coefficients are estimated as a function of the angle between the rotor and the wind direction. This representation of the aerodynamic loading on the RNA was then verified against full-field turbulent wind simulations in fixed and floating conditions using a multi-megawatt commercial turbine. The results for the parameters concerning the floater, mooring and marine operations design were monitored (e.g. tower bottom loads, offsets, pitch, mooring tensions) for extreme conditions and the errors introduced by this simplified rotor are generally lower than 4%. This illustrates that this simplified representation of the turbine can be used by the various parties of the project during the early stages of the design, particularly when knowing the loading within the RNA and on higher sections of the tower is not important.
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Ruiz Toledo, Maria Mercedes. „Propuesta de material didáctico desde el diseño visual acotado en la inclusión y el entorno educativo infantil autista del centro Neurokids“. In Encuentro de investigación formativa en Diseño – Semilleros y Grupos de investigación RAD 2019. Pasto, Colombia: Red Académica de Diseño - RAD, 2019. http://dx.doi.org/10.53972/rad.eifd.2019.2.5.
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La mejora en la educación visual y gráfica de los niños y niñas de 6 a 10 años con Trastorno del Espectro Autista (TEA), unida al aprendizaje lúdico, son los dos temas que impulsan el proyecto, con la elaboración de un material didáctico que logra mejorar tanto la enseñanza como su aprendizaje, en el Centro de Rehabilitación Infantil Neurokids, con el fin de suplir la necesidad principal, la cual es la ausencia de material didáctico; por esto a los niños y niñas con este trastorno, se les dificulta el aprendizaje de los temas educativos. Se desarrolló el design thinking como proceso metodológico, pues éste ayuda a generar una solución más precisa a la necesidad y deseo de la población objetivo, ya que permite recolectar información sobre el grupo poblacional, con la finalidad de tener una participación activa e información completa y precisa. Como principal resultado, se obtuvo la mejora tanto de la enseñanza como del aprendizaje, gracias al prototipo -material didáctico- que se elaboró, además de mejorar la comunicación y motivación por aprender temas como: geografía, ortografía, abecedario y matemáticas, al tener en cuenta los elementos visuales y la teoría de inteligencias múltiples formulada por Howard Gardner (1983). Es importante destacar, que el manejo de materiales didácticos físicos, es relevante en el proceso educativo de niños y niñas con autismo, puesto que ayuda a disminuir su aislamiento y aumenta su motivación por aprender.