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Journal articles on the topic 'Proteolysis targeting chimera (PROTAC)'

Author: Grafiati

Published: 4 June 2021

Last updated: 1 February 2022

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1

Wan, Yichao, Chunxing Yan, Han Gao, and Tingting Liu. "Small-molecule PROTACs: novel agents for cancer therapy." Future Medicinal Chemistry 12, no. 10 (2020): 915–38. http://dx.doi.org/10.4155/fmc-2019-0340.

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Proteolysis-targeting chimera (PROTAC) is a new technology to selectively degrade target proteins via ubiquitin-proteasome system. PROTAC molecules (PROTACs) are a class of heterobifunctional molecules, which contain a ligand targeting the protein of interest, a ligand recruiting an E3 ligase and a linker connecting these two ligands. They provide several advantages over traditional inhibitors in potency, selectivity and drug resistance. Thus, many promising PROTACs have been developed in the recent two decades, especially small-molecule PROTACs. In this review, we briefly introduce the mechan

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2

Smalley, Joshua P., Grace E. Adams, Christopher J. Millard, et al. "PROTAC-mediated degradation of class I histone deacetylase enzymes in corepressor complexes." Chemical Communications 56, no. 32 (2020): 4476–79. http://dx.doi.org/10.1039/d0cc01485k.

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We have identified a proteolysis targeting chimera (PROTAC) of class I HDACs 1, 2 and 3. Our PROTAC decreased HDAC 1, 2 & 3 protein abundance, increased histone acetylation levels and compromised colon cancer HCT116 cell viability.

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Robb, Caroline M., Jacob I. Contreras, Smit Kour, et al. "Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC)." Chemical Communications 53, no. 54 (2017): 7577–80. http://dx.doi.org/10.1039/c7cc03879h.

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Xia, Li-Wen, Meng-Yu Ba, Wei Liu, et al. "Triazol: a privileged scaffold for proteolysis targeting chimeras." Future Medicinal Chemistry 11, no. 22 (2019): 2919–73. http://dx.doi.org/10.4155/fmc-2019-0159.

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Current traditional drugs such as enzyme inhibitors and receptor agonists/antagonists present inherent limitations due to occupancy-driven pharmacology as the mode of action. Proteolysis targeting chimeras (PROTACs) are composed of an E3 ligand, a connecting linker and a target protein ligand, and are an attractive approach to specifically knockdown-targeted proteins utilizing an event-driven mode of action. The length, hydrophilicity and rigidity of connecting linkers play important role in creating a successful PROTAC. Some PROTACs with a triazole linker have displayed promising anticancer a

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Cimas, Francisco J., Enrique Niza, Alberto Juan, et al. "Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer." Pharmaceutics 12, no. 10 (2020): 986. http://dx.doi.org/10.3390/pharmaceutics12100986.

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Bromo and extraterminal domain (BET) inhibitors-PROteolysis TArgeting Chimera (BETi-PROTAC) is a new family of compounds that induce proteasomal degradation through the ubiquitination of the tagged to BET inhibitors Bromodomain proteins, BRD2 and BRD. The encapsulation and controlled release of BET-PROTACs through their vectorization with antibodies, like trastuzumab, could facilitate their pharmacokinetic and efficacy profile. Antibody conjugated nanoparticles (ACNPs) using PROTACs have not been designed and evaluated. In this pioneer approach, the commercial MZ1 PROTAC was encapsulated into

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Koravović, Mladen, Gordana Tasić, Milena Rmandić, and Bojan Marković. "Photocontrollable PROTAC molecules: Structure and mechanism of action." Arhiv za farmaciju 71, no. 3 (2021): 161–76. http://dx.doi.org/10.5937/arhfarm71-30785.

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Traditional drug discovery strategies are usually focused on occupancy of binding sites that directly affect functions of proteins. Hence, proteins that lack such binding sites are generally considered pharmacologically intractable. Modulators of protein activity, especially inhibitors, must be applied in appropriate dosage regimens that often lead to high systemic drug exposures in order to maintain sufficient protein inhibition in vivo. Consequently, there is a risk of undesirable off-target drug binding and side effects. Recently, PROteolysis TArgeting Chimera (PROTAC) technology has emerge

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Liu, Jing, He Chen, Leina Ma, et al. "Light-induced control of protein destruction by opto-PROTAC." Science Advances 6, no. 8 (2020): eaay5154. http://dx.doi.org/10.1126/sciadv.aay5154.

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By hijacking endogenous E3 ligase to degrade protein targets via the ubiquitin-proteasome system, PROTACs (PRoteolysis TArgeting Chimeras) provide a new strategy to inhibit protein targets that were regarded as undruggable before. However, the catalytic nature of PROTAC potentially leads to uncontrolled degradation that causes systemic toxicity issues, limiting the application of PROTAC in the clinic. Here, we introduce a light-inducible switch on PROTACs, thereafter termed as opto-PROTAC, to enable the degradation of protein targets in a spatiotemporal manner. By adding a photolabile caging g

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Wang, Pingyuan, and Jia Zhou. "Proteolysis Targeting Chimera (PROTAC): A Paradigm-Shifting Approach in Small Molecule Drug Discovery." Current Topics in Medicinal Chemistry 18, no. 16 (2018): 1354–56. http://dx.doi.org/10.2174/1568026618666181010101922.

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Cao, Fangyuan, Sander de Weerd, Deng Chen, Martijn R. H. Zwinderman, Petra E. van der Wouden, and Frank J. Dekker. "Induced protein degradation of histone deacetylases 3 (HDAC3) by proteolysis targeting chimera (PROTAC)." European Journal of Medicinal Chemistry 208 (December 2020): 112800. http://dx.doi.org/10.1016/j.ejmech.2020.112800.

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Zeng, Shenxin, Wenhai Huang, Xiaoliang Zheng, et al. "Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges." European Journal of Medicinal Chemistry 210 (January 2021): 112981. http://dx.doi.org/10.1016/j.ejmech.2020.112981.

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11

Du, M., G. Wang, T. M. Ismail, et al. "Proteolysis-targeting chimera (PROTAC) compounds to degrade S100A4 and inhibit breast cancer metastasis." Annals of Oncology 29 (November 2018): ix20. http://dx.doi.org/10.1093/annonc/mdy428.020.

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12

Kang, Chung Hyo, Dong Ho Lee, Chong Ock Lee, Jae Du Ha, Chi Hoon Park, and Jong Yeon Hwang. "Induced protein degradation of anaplastic lymphoma kinase (ALK) by proteolysis targeting chimera (PROTAC)." Biochemical and Biophysical Research Communications 505, no. 2 (2018): 542–47. http://dx.doi.org/10.1016/j.bbrc.2018.09.169.

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13

Krajcovicova, S., R. Jorda, D. Hendrychova, V. Krystof, and M. Soural. "Solid-phase synthesis for thalidomide-based proteolysis-targeting chimeras (PROTAC)." Chemical Communications 55, no. 7 (2019): 929–32. http://dx.doi.org/10.1039/c8cc08716d.

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14

Weng, Gaoqi, Chao Shen, Dongsheng Cao, et al. "PROTAC-DB: an online database of PROTACs." Nucleic Acids Research 49, no. D1 (2020): D1381—D1387. http://dx.doi.org/10.1093/nar/gkaa807.

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Abstract Proteolysis-targeting chimeras (PROTACs), which selectively degrade targeted proteins by the ubiquitin-proteasome system, have emerged as a novel therapeutic technology with potential advantages over traditional inhibition strategies. In the past few years, this technology has achieved substantial progress and two PROTACs have been advanced into phase I clinical trials. However, this technology is still maturing and the design of PROTACs remains a great challenge. In order to promote the rational design of PROTACs, we present PROTAC-DB, a web-based open-access database that integrates

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Chen, Yilin, and Jianping Jin. "The application of ubiquitin ligases in the PROTAC drug design." Acta Biochimica et Biophysica Sinica 52, no. 7 (2020): 776–90. http://dx.doi.org/10.1093/abbs/gmaa053.

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Abstract Protein ubiquitylation plays important roles in many biological activities. Protein ubiquitylation is a unique process that is mainly controlled by ubiquitin ligases. The ubiquitin-proteasome system (UPS) is the main process to degrade short-lived and unwanted proteins in eukaryotes. Many components in the UPS are attractive drug targets. Recent studies indicated that ubiquitin ligases can be employed as tools in proteolysis-targeting chimeras (PROTACs) for drug discovery. In this review article, we will discuss the recent progress of the application of ubiquitin ligases in the PROTAC

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Kim, Ga Yeong, Chae Won Song, Yo-Sep Yang, et al. "Chemical Degradation of Androgen Receptor (AR) Using Bicalutamide Analog–Thalidomide PROTACs." Molecules 26, no. 9 (2021): 2525. http://dx.doi.org/10.3390/molecules26092525.

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A series of PROTACs (PROteolysis-TArgeting Chimeras) consisting of bicalutamide analogs and thalidomides were designed, synthesized, and biologically evaluated as novel androgen receptor (AR) degraders. In particular, we found that PROTAC compound 13b could successfully demonstrate a targeted degradation of AR in AR-positive cancer cells and might be a useful chemical probe for the investigation of AR-dependent cancer cells, as well as a potential therapeutic candidate for prostate cancers.

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Zhang, Hao, Hong-Yi Zhao, Xiao-Xiao Xi, et al. "Discovery of potent epidermal growth factor receptor (EGFR) degraders by proteolysis targeting chimera (PROTAC)." European Journal of Medicinal Chemistry 189 (March 2020): 112061. http://dx.doi.org/10.1016/j.ejmech.2020.112061.

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18

Manda, Sudhakar, Na Keum Lee, Dong-Chan Oh, and Jeeyeon Lee. "Design, Synthesis, and Biological Evaluation of Proteolysis Targeting Chimeras (PROTACs) for the Dual Degradation of IGF-1R and Src." Molecules 25, no. 8 (2020): 1948. http://dx.doi.org/10.3390/molecules25081948.

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A focused PROTAC library was developed to degrade both IGF-1R and Src proteins, which are associated with various cancers. PROTACs with IGF-1R and Src degradation potentials were synthesized by tethering different inhibitor warhead units and the E3 ligase (CRBN) recruiting-pomalidomide with various linkers. The designed PROTACs 12a–b inhibited the proliferation and migration of MCF7 and A549 cancer cells with low micromolar potency (1–5 μM) in various cellular assays.

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19

Gütschow, Michael, Christian Steinebach, Sabine Anna Voell, et al. "A Facile Synthesis of Ligands for the von Hippel–Lindau E3 Ligase." Synthesis 52, no. 17 (2020): 2521–27. http://dx.doi.org/10.1055/s-0040-1707400.

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The proteolysis-targeting chimeras (PROTACs) have become an integral part of different stages of drug discovery. This growing field, therefore, benefits from advancements in all segments of the design of these compounds. Herein, an efficient and optimized synthetic protocol to various von Hippel-Lindau (VHL) ligands is presented, which enables easy access to multigram quantities of these essential PROTAC building blocks. Moreover, the elaborated synthesis represents a straightforward approach to further explore the chemical space of VHL ligands.

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20

Galdeano, Carles. "Expanding the Toolbox of E3 Ligases for Protein Degradation: Targeting the “Undruggable” Fbw7 E3 Ligase." Proceedings 22, no. 1 (2019): 101. http://dx.doi.org/10.3390/proceedings2019022101.

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21

Zagidullin, Almaz, Vasili Milyukov, Albert Rizvanov, and Emil Bulatov. "Novel approaches for the rational design of PROTAC linkers." Exploration of Targeted Anti-tumor Therapy 1, no. 5 (2020): 381–90. http://dx.doi.org/10.37349/etat.2020.00023.

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Proteolysis targeting chimeras (PROTACs) represent a promising class of hetero-bivalent molecules that facilitate ubiquitination of a target protein by simultaneously binding and bringing together both the E3 enzyme and the target. These compounds consist of three structural components: two ligands one of which binds the protein of interest (POI) while the other binds an E3 ubiquitin ligase to promote POI ubiquitination, and a linker connecting both moieties. Recent developments in the field highlight the fact that linker composition and length play a crucial role in achieving optimal PROTAC p

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22

Sun, B., W. Fiskus, Y. Qian, et al. "BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells." Leukemia 32, no. 2 (2017): 343–52. http://dx.doi.org/10.1038/leu.2017.207.

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23

Hu, Mingxing, Weilin Zhou, Yijie Wang, et al. "Discovery of the first potent proteolysis targeting chimera (PROTAC) degrader of indoleamine 2,3-dioxygenase 1." Acta Pharmaceutica Sinica B 10, no. 10 (2020): 1943–53. http://dx.doi.org/10.1016/j.apsb.2020.02.010.

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24

Xiang, Wang, Qiwei Wang, Kai Ran, Jing Ren, Yaojie Shi, and Luoting Yu. "Structure-guided discovery of novel potent and efficacious proteolysis targeting chimera (PROTAC) degrader of BRD4." Bioorganic Chemistry 115 (October 2021): 105238. http://dx.doi.org/10.1016/j.bioorg.2021.105238.

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25

Saenz, Dyana T., Warren Fiskus, Kanak Raina, et al. "Superior Lethal Activity of Novel BET Protein Proteolysis Targeting Chimera (BETP-PROTACs) Versus Betp Bromodomain Inhibitor (BETi) Against Post-Myeloproliferative Neoplasm (MPN) Secondary (s) AML Cells." Blood 128, no. 22 (2016): 747. http://dx.doi.org/10.1182/blood.v128.22.747.747.

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Abstract Hematopoietic stem/progenitor cells (HPCs) of BCR-ABL1-negative myeloproliferative neoplasms with myelofibrosis (MPN-MF) exhibit mutations in JAK2, c-MPL, or calreticulin (CALR) gene and display constitutive activation of JAK-STAT signaling. In MPN-MF, transformation to AML (sAML) occurs in up to 20% of patients. Ruxolitinib (R) is a type I, ATP-competitive, JAK1 & 2 inhibitor (JAKi), which is currently used in the therapy of MPN-MF. Treatment with R confers notable clinical benefit in MPN-MF, but exhibits only modest activity and does not significantly impact the clinical outcome

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Xia, Liwen, Wei Liu, Yinsen Song, Hailiang Zhu, and Yongtao Duan. "The Present and Future of Novel Protein Degradation Technology." Current Topics in Medicinal Chemistry 19, no. 20 (2019): 1784–88. http://dx.doi.org/10.2174/1568026619666191011162955.

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Proteolysis targeting chimeras (PROTACs), as a novel therapeutic modality, play a vital role in drug discovery. Each PROTAC contains three key parts; a protein-of-interest (POI) ligand, a E3 ligase ligand, and a linker. These bifunctional molecules could mediate the degradation of POIs by hijacking the activity of E3 ubiquitin ligases for POI ubiquitination and subsequent degradation via the ubiquitin proteasome system (UPS). With several advantages over other therapeutic strategies, PROTACs have set off a new upsurge of drug discovery in recent years. ENDTAC, as the development of PROTACs tec

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Hu, Jiantao, Biao Hu, Mingliang Wang, et al. "Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER)." Journal of Medicinal Chemistry 62, no. 3 (2019): 1420–42. http://dx.doi.org/10.1021/acs.jmedchem.8b01572.

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28

Semenova, Elizaveta, Maria Luisa Guerriero, Bairu Zhang, et al. "Flexible Fitting of PROTAC Concentration–Response Curves with Changepoint Gaussian Processes." SLAS DISCOVERY: Advancing the Science of Drug Discovery 26, no. 9 (2021): 1212–24. http://dx.doi.org/10.1177/24725552211028142.

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A proteolysis-targeting chimera (PROTAC) is a new technology that marks proteins for degradation in a highly specific manner. During screening, PROTAC compounds are tested in concentration–response (CR) assays to determine their potency, and parameters such as the half-maximal degradation concentration (DC50) are estimated from the fitted CR curves. These parameters are used to rank compounds, with lower DC50 values indicating greater potency. However, PROTAC data often exhibit biphasic and polyphasic relationships, making standard sigmoidal CR models inappropriate. A common solution includes

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Giardina, Sarah F., Elena Valdambrini, J. David Warren, and Francis Barany. "PROTACs: Promising Approaches for Epigenetic Strategies to Overcome Drug Resistance." Current Cancer Drug Targets 21, no. 4 (2021): 306–25. http://dx.doi.org/10.2174/1568009621666210203110857.

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Epigenetic modulation of gene expression is essential for tissue-specific development and maintenance in mammalian cells. Disruption of epigenetic processes, and the subsequent alteration of gene functions, can result in inappropriate activation or inhibition of various cellular signaling pathways, leading to cancer. Recent advancements in the understanding of the role of epigenetics in cancer initiation and progression have uncovered functions for DNA methylation, histone modifications, nucleosome positioning, and non-coding RNAs. Epigenetic therapies have shown some promise for hematological

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Bao, Shui-Ming, Qing-Hui Hu, Wen-Ting Yang, Yao Wang, Yin-Ping Tong, and Wen-Dai Bao. "Targeting Epidermal Growth Factor Receptor in Non-Small-Cell-Lung Cancer: Current State and Future Perspective." Anti-Cancer Agents in Medicinal Chemistry 19, no. 8 (2019): 984–91. http://dx.doi.org/10.2174/1871520619666190313161009.

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Background: Lung cancer is one of the leading cause of cancer death worldwide, the most common histological type of lung cancer is non-small cell lung cancer (NSCLC), whose occurrence and development is closely related to the mutation and amplification of epidermal growth factor receptors (EGFR). Currently , a series of targeted drugs were developed on the inhibition of EGFR such as epidermal growth factor receptortyrosine kinase inhibitor EGFR-TKI and monoclonal antibody (McAb). Objective: We sought to summarizes the current drugs targeting Epidermal Growth Factor Receptor in nonsmall- cell-l

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Porazzi, Patrizia, Marco De Dominici, Joseph Salvino, and Bruno Calabretta. "Targeting the CDK6 Dependence of Ph+ Acute Lymphoblastic Leukemia." Genes 12, no. 9 (2021): 1355. http://dx.doi.org/10.3390/genes12091355.

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Ph+ ALL is a poor-prognosis leukemia subtype driven by the BCR-ABL1 oncogene, either the p190- or the p210-BCR/ABL isoform in a 70:30 ratio. Tyrosine Kinase inhibitors (TKIs) are the drugs of choice in the therapy of Ph+ ALL. In combination with standard chemotherapy, TKIs have markedly improved the outcome of Ph+ ALL, in particular if this treatment is followed by bone marrow transplantation. However, resistance to TKIs develops with high frequency, causing leukemia relapse that results in <5-year overall survival. Thus, new therapies are needed to address relapsed/TKI-resistant Ph+ ALL. W

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Wei, Mingming, Rui Zhao, Yuting Cao, et al. "First orally bioavailable prodrug of proteolysis targeting chimera (PROTAC) degrades cyclin-dependent kinases 2/4/6 in vivo." European Journal of Medicinal Chemistry 209 (January 2021): 112903. http://dx.doi.org/10.1016/j.ejmech.2020.112903.

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Xiao, Zhangping, Shanshan Song, Deng Chen, et al. "Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells." Angewandte Chemie International Edition 60, no. 32 (2021): 17514–21. http://dx.doi.org/10.1002/anie.202101864.

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Xiao, Zhangping, Shanshan Song, Deng Chen, et al. "Proteolysis Targeting Chimera (PROTAC) for Macrophage Migration Inhibitory Factor (MIF) Has Anti‐Proliferative Activity in Lung Cancer Cells." Angewandte Chemie 133, no. 32 (2021): 17655–62. http://dx.doi.org/10.1002/ange.202101864.

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He, Yonghan, Raphael Koch, Vivekananda Budamagunta, et al. "DT2216, a BCL-XL Proteolysis Targeting Chimera (PROTAC), Is a Potent Anti T-Cell Lymphoma Agent That Does Not Induce Significant Thrombocytopenia." Blood 134, Supplement_1 (2019): 303. http://dx.doi.org/10.1182/blood-2019-125820.

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There is an urgent need for new therapeutic agents to treat patients with T-cell lymphoma (TCL). Multiple hematologic malignancies evade apoptosis through overexpression of anti-apoptotic proteins in the BCL-2 family, including BCL-2, BCL-XL, and MCL-1. We and others recently showed that a large fraction of cutaneous and peripheral TCL cell lines, patient-derived xenografts and primary patient samples depend on BCL-XL for survival (Koch et al, Blood. 2019; 133:566-575). These findings suggest that targeted inhibition of BCL-XL could offer therapeutic benefit for some TCL patients. Currently av

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Neklesa, Taavi, Lawrence B. Snyder, Ryan R. Willard, et al. "An oral androgen receptor PROTAC degrader for prostate cancer." Journal of Clinical Oncology 36, no. 6_suppl (2018): 381. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.381.

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381 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology

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Neklesa, Taavi K., Lawrence B. Snyder, Mark Bookbinder, et al. "An oral androgen receptor PROTAC degrader for prostate cancer." Journal of Clinical Oncology 35, no. 6_suppl (2017): 273. http://dx.doi.org/10.1200/jco.2017.35.6_suppl.273.

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273 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology

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Fuchs, Ota, and Radka Bokorova. "Preclinical Studies of PROTACs in Hematological Malignancies." Cardiovascular & Hematological Disorders-Drug Targets 21, no. 1 (2021): 7–22. http://dx.doi.org/10.2174/1871529x21666210308111546.

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Incorrectly expressed or mutated proteins associated with hematologic malignancies have been generally targeted by chemotherapy using small-molecule inhibitors or monoclonal antibodies. But the majority of these intracellular proteins are without active sites and antigens. PROTACs, proteolysis targeting chimeras, are bifunctional molecules designed to polyubiquitinate and degrade specific pathological proteins of interest (POIs) by hijacking the activity of E3-ubiquitin ligases for POI polyubiquitination and subsequent degradation by the proteasome. This strategy utilizes the ubiquitin-proteas

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Schiedel, Matthias, Daniel Herp, Sören Hammelmann, et al. "Chemically Induced Degradation of Sirtuin 2 (Sirt2) by a Proteolysis Targeting Chimera (PROTAC) Based on Sirtuin Rearranging Ligands (SirReals)." Journal of Medicinal Chemistry 61, no. 2 (2017): 482–91. http://dx.doi.org/10.1021/acs.jmedchem.6b01872.

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Chen, Linrong, Liuquan Han, Shujun Mao, et al. "Discovery of A031 as effective proteolysis targeting chimera (PROTAC) androgen receptor (AR) degrader for the treatment of prostate cancer." European Journal of Medicinal Chemistry 216 (April 2021): 113307. http://dx.doi.org/10.1016/j.ejmech.2021.113307.

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Piya, Sujan, Hong Mu, Seemana Bhattacharya, et al. "BRD4 Proteolysis Targeting Chimera (PROTAC) ARV-825 Targets Both NOTCH1-MYC Regulatory Circuit and Leukemia-Microenvironment in T-ALL." Blood 130, Suppl_1 (2017): 716. http://dx.doi.org/10.1182/blood.v130.suppl_1.716.716.

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Abstract Background: Salvage options for patients with relapsed T cell acute lymphoblastic leukemia (T-ALL) are limited, with less than 25% of these patients achieving second remission 1, 2. 70% of T-ALL cases have activating mutations of the NOTCH1 pathway, which transcriptionally activates MYC by binding to its `superenhancer' region 3, 4. Other deregulated oncogenic pathways in T-ALL include PI3K/Akt, the anti-apoptotic Bcl-2 family, and CDKN2A/2B cell cycle regulators 5, 6. The NOTCH1-MYC regulatory circuit is an attractive therapeutic target, but clinical development of gamma-secretase in

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Bollu, Lakshmi, Derek Wainwright, Lijie Zhai, et al. "DDRE-09. DEVELOPING IDO-PROTACS TO IMPROVE IMMUNOTHERAPEUTIC EFFICACY IN PATIENTS WITH GLIOBLASTOMA." Neuro-Oncology 22, Supplement_2 (2020): ii63. http://dx.doi.org/10.1093/neuonc/noaa215.254.

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Abstract INTRODUCTION Indoleamine 2,3-dioxygenase 1 (IDO; IDO1) is a rate-limiting enzyme that metabolizes the essential amino acid tryptophan into kynurenine. Recent work by our group has revealed that IDO promotes tumor development and suppresses immune cell functions independent of its enzyme activity. Moreover, pharmacologic IDO enzyme inhibitors that currently serve as the only class of drugs available for targeting immunosuppressive IDO activity, fail to improve the survival of patients with GBM. Here, we developed IDO-Proteolysis Targeting Chimeras (IDO-PROTACs). PROTACs bind to a speci

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Zorba, Adelajda, Chuong Nguyen, Yingrong Xu, et al. "Delineating the role of cooperativity in the design of potent PROTACs for BTK." Proceedings of the National Academy of Sciences 115, no. 31 (2018): E7285—E7292. http://dx.doi.org/10.1073/pnas.1803662115.

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Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously “undruggable” targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series o

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Márquez-Cantudo, Laura, Ana Ramos, Claire Coderch, and Beatriz de Pascual-Teresa. "Proteasomal Degradation of Zn-Dependent Hdacs: The E3-Ligases Implicated and the Designed Protacs that Enable Degradation." Molecules 26, no. 18 (2021): 5606. http://dx.doi.org/10.3390/molecules26185606.

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Protein degradation by the Ubiquitin-Proteasome System is one of the main mechanisms of the regulation of cellular proteostasis, and the E3 ligases are the key effectors for the protein recognition and degradation. Many E3 ligases have key roles in cell cycle regulation, acting as checkpoints and checkpoint regulators. One of the many important proteins involved in the regulation of the cell cycle are the members of the Histone Deacetylase (HDAC) family. The importance of zinc dependent HDACs in the regulation of chromatin packing and, therefore, gene expression, has made them targets for the

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Lim, Shuhui, Regina Khoo, Khong Ming Peh, et al. "bioPROTACs as versatile modulators of intracellular therapeutic targets including proliferating cell nuclear antigen (PCNA)." Proceedings of the National Academy of Sciences 117, no. 11 (2020): 5791–800. http://dx.doi.org/10.1073/pnas.1920251117.

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Targeted degradation approaches such as proteolysis targeting chimeras (PROTACs) offer new ways to address disease through tackling challenging targets and with greater potency, efficacy, and specificity over traditional approaches. However, identification of high-affinity ligands to serve as PROTAC starting points remains challenging. As a complementary approach, we describe a class of molecules termed biological PROTACs (bioPROTACs)—engineered intracellular proteins consisting of a target-binding domain directly fused to an E3 ubiquitin ligase. Using GFP-tagged proteins as model substrates,

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Huang, Xiaohu, Yan Liu, Yin Wang, Christopher Bailey, Pan Zheng та Yang Liu. "Dual Targeting Oncoproteins MYC and HIF1α Regresses Tumor Growth of Lung Cancer and Lymphoma". Cancers 13, № 4 (2021): 694. http://dx.doi.org/10.3390/cancers13040694.

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MYC and HIF1α are among the most important oncoproteins whose pharmacologic inhibition has been challenging for the diverse mechanisms driving their abnormal expression and because of the challenge in blocking protein-DNA interactions. Surprisingly, we found that MYC and HIF1α proteins in echinomycin-treated cells were degraded through proteasome dependent pathways, respectively by the β-TrCP- or VHL-dependent mechanisms. The degradation is induced in a variety of cancer types, including those with mutations in the p53 tumor and LKB tumor suppressors and the KRAS oncogene. Consistent with inhi

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Sun, Baohua, Warren Fiskus, Liang Zhang, et al. "Novel BET Protein Proteolysis Targeting Chimeras (BETP-PROTACs) Exert Potent Single Agent and Synergistic Activity with Ibrutinib and Venetoclax Against Human Mantle Cell Lymphoma Cells." Blood 128, no. 22 (2016): 1058. http://dx.doi.org/10.1182/blood.v128.22.1058.1058.

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Abstract Mantle Cell Lymphoma (MCL) exhibits pathogenetic mutations or deletion of RB1, ATM, p53, deletion of INK4a/ARF, as well as copy number gains of MYC, CDK4 and BCL2. Activated B cell receptor (BCR) signaling, and the ensuing downstream pro-growth and pro-survival NFkB activity, is also a notable feature of MCL. Collectively, the genetic alterations and the ensuing deregulated signaling and activity of transcription factors, including c-MYC and NFkB, creates the MCL-specific 'transcriptome' that promotes growth and survival of MCL cells. Ibrutinib, a covalent inhibitor of Bruton's tyrosi

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Wang, Yubo, Yuanyuan Zhou, Sheng Cao, et al. "In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC)." Bioorganic Chemistry 111 (June 2021): 104833. http://dx.doi.org/10.1016/j.bioorg.2021.104833.

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Mologni, Luca, Giovanni Marzaro, Sara Redaelli, and Alfonso Zambon. "Dual Kinase Targeting in Leukemia." Cancers 13, no. 1 (2021): 119. http://dx.doi.org/10.3390/cancers13010119.

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Pharmacological cancer therapy is often based on the concurrent inhibition of different survival pathways to improve treatment outcomes and to reduce the risk of relapses. While this strategy is traditionally pursued only through the co-administration of several drugs, the recent development of multi-targeting drugs (i.e., compounds intrinsically able to simultaneously target several macromolecules involved in cancer onset) has had a dramatic impact on cancer treatment. This review focuses on the most recent developments in dual-kinase inhibitors used in acute myeloid leukemia (AML), chronic m

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Pang, Xiao-Jing, Xiu-Juan Liu, Yuan Liu, et al. "Drug Discovery Targeting Focal Adhesion Kinase (FAK) as a Promising Cancer Therapy." Molecules 26, no. 14 (2021): 4250. http://dx.doi.org/10.3390/molecules26144250.

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FAK is a nonreceptor intracellular tyrosine kinase which plays an important biological function. Many studies have found that FAK is overexpressed in many human cancer cell lines, which promotes tumor cell growth by controlling cell adhesion, migration, proliferation, and survival. Therefore, targeting FAK is considered to be a promising cancer therapy with small molecules. Many FAK inhibitors have been reported as anticancer agents with various mechanisms. Currently, six FAK inhibitors, including GSK-2256098 (Phase I), VS-6063 (Phase II), CEP-37440 (Phase I), VS-6062 (Phase I), VS-4718 (Phase

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