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Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins.

Chen D, Lu T, Yan Z, Lu W, Zhou F, Lyu X, Xu B, Jiang H, Chen K, Luo C, Zhao Y
Eur J Med Chem 182 111633 (2019)
Cited: 13 times
EuropePMC logo PMID: 31461688

Abstract

Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.

Reviews citing this publication (9)

  1. Inhibitors of bromodomain and extra-terminal proteins for treating multiple human diseases. Kulikowski E, Rakai BD, Wong NCW. Med Res Rev 41 223-245 (2021)
  2. The application of histone deacetylases inhibitors in glioblastoma. Chen R, Zhang M, Zhou Y, Guo W, Yi M, Zhang Z, Ding Y, Wang Y. J Exp Clin Cancer Res 39 138 (2020)
  3. Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development. Tang P, Zhang J, Liu J, Chiang CM, Ouyang L. J Med Chem 64 2419-2435 (2021)
  4. A Comprehensive Review of BET Protein Biochemistry, Physiology, and Pathological Roles. Ali HA, Li Y, Bilal AHM, Qin T, Yuan Z, Zhao W. Front Pharmacol 13 818891 (2022)
  5. Recent progress and structural analyses of domain-selective BET inhibitors. Divakaran A, Harki DA, Pomerantz WCK. Med Res Rev 43 972-1018 (2023)
  6. Bromodomain and extraterminal (BET) proteins: biological functions, diseases, and targeted therapy. Wang ZQ, Zhang ZC, Wu YY, Pi YN, Lou SH, Liu TB, Lou G, Yang C. Signal Transduct Target Ther 8 420 (2023)
  7. Improving TRAIL-induced apoptosis in cancers by interfering with histone modifications. Zhang BJ, Chen D, Dekker FJ, Quax WJ. Cancer Drug Resist 3 791-803 (2020)
  8. Bromodomain inhibitors and therapeutic applications. Gajjela BK, Zhou MM. Curr Opin Chem Biol 75 102323 (2023)
  9. Targeting bromodomain-containing proteins: research advances of drug discovery. Pan Z, Zhao Y, Wang X, Xie X, Liu M, Zhang K, Wang L, Bai D, Foster LJ, Shu R, He G. Mol Biomed 4 13 (2023)

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