Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA, USA.
Constellation Pharmaceuticals, Cambridge, MA, USA.
Nat Rev Drug Discov. 2019 Aug;18(8):609-628. doi: 10.1038/s41573-019-0030-7. Epub 2019 Jul 4.
Less than a decade ago, it was shown that bromodomains, acetyl lysine 'reader' modules found in proteins with varied functions, were highly tractable small-molecule targets. This is an unusual property for protein-protein or protein-peptide interaction domains, and it prompted a wave of chemical probe discovery to understand the biological potential of new agents that targeted bromodomains. The original examples, inhibitors of the bromodomain and extra-terminal (BET) class of bromodomains, showed enticing anti-inflammatory and anticancer activities, and several compounds have since advanced to human clinical trials. Here, we review the current state of BET inhibitor biology in relation to clinical development, and we discuss the next wave of bromodomain inhibitors with clinical potential in oncology and non-oncology indications. The lessons learned from BET inhibitor programmes should affect efforts to develop drugs that target non-BET bromodomains and other epigenetic readers.
不到十年前，人们发现溴结构域（存在于具有多种功能的蛋白质中的乙酰赖氨酸“读取”模块）是高度可成药的小分子靶标。这对于蛋白质-蛋白质或蛋白质-肽相互作用结构域来说是一种不寻常的特性，这促使了一波化学探针的发现，以了解靶向溴结构域的新型试剂的生物学潜力。最初的例子是溴结构域和末端（BET）类溴结构域抑制剂，它们表现出诱人的抗炎和抗癌活性，此后有几种化合物已进入人体临床试验。在这里，我们回顾了 BET 抑制剂生物学在临床开发方面的现状，并讨论了具有肿瘤学和非肿瘤学适应证临床潜力的下一波溴结构域抑制剂。从 BET 抑制剂项目中吸取的经验教训应该会影响开发靶向非 BET 溴结构域和其他表观遗传读取器的药物的努力。
