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发现苯并[d]咪唑-6-磺酰胺类化合物作为溴结构域和额外末端结构域（BET）抑制剂，对第一个溴结构域具有选择性。

Discovery of Benzo[d]imidazole-6-sulfonamides as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain.

机构信息

Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084, Fisciano (SA), Italy.

Nuffield Department of Medicine, Oxford University, OX3 7DQ, Oxford, UK.

出版信息

ChemMedChem. 2022 Oct 19;17(20):e202200343. doi: 10.1002/cmdc.202200343. Epub 2022 Sep 15.

DOI:10.1002/cmdc.202200343
PMID:36040095
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9826262/
Abstract

The bromodomain and extra-terminal (BET) family of proteins includes BRD2, BRD3, BRD4, and the testis-specific protein, BRDT, each containing two N-terminal tandem bromodomain (BRD) modules. Potent and selective inhibitors targeting the two bromodomains are required to elucidate their biological role(s), with potential clinical applications. In this study, we designed and synthesized a series of benzimidazole-6-sulfonamides starting from the azobenzene compounds MS436 (7 a) and MS611 (7 b) that exhibited preference for the first (BD1) over the second (BD2) BRD of BET family members. The most-promising compound (9 a) showed good binding potency and improved metabolic stability and selectivity towards BD1 with respect to the parent compounds.

摘要

溴结构域和末端（BET）蛋白家族包括 BRD2、BRD3、BRD4 和睾丸特异性蛋白 BRDT，每个蛋白都包含两个 N 端串联溴结构域（BRD）模块。需要针对两个溴结构域设计和合成有效的、选择性的抑制剂，以阐明它们的生物学作用，并具有潜在的临床应用价值。在这项研究中，我们以对 BET 家族成员的第一个（BD1）比第二个（BD2）BRD 具有偏好性的偶氮苯化合物 MS436（7a）和 MS611（7b）为起点，设计并合成了一系列苯并咪唑-6-磺酰胺。最有前景的化合物（9a）与母体化合物相比，显示出良好的结合效力和改善的代谢稳定性及对 BD1 的选择性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c61e/9826262/5c8ddbc096fa/CMDC-17-0-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c61e/9826262/5c8ddbc096fa/CMDC-17-0-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c61e/9826262/f1911bbd1ebd/CMDC-17-0-g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c61e/9826262/ed74c6c75344/CMDC-17-0-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c61e/9826262/ffc2ceefb6e2/CMDC-17-0-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c61e/9826262/1521b8477413/CMDC-17-0-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c61e/9826262/c0dcc839c186/CMDC-17-0-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c61e/9826262/5c8ddbc096fa/CMDC-17-0-g010.jpg

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Discovery of 1-(5-(1H-benzo[d]imidazole-2-yl)-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one derivatives as novel and potent bromodomain and extra-terminal (BET) inhibitors with anticancer efficacy.发现 1-(5-(1H-苯并[d]咪唑-2-基)-2,4-二甲基-1H-吡咯-3-基)乙-1-酮衍生物具有新型强效溴结构域和末端结构域（BET）抑制作用和抗癌功效。
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