Constellation, a Morphosys Company, 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
J Med Chem. 2022 Aug 25;65(16):11177-11186. doi: 10.1021/acs.jmedchem.2c00662. Epub 2022 Aug 5.
Bromodomains are acetyllysine recognition domains present in a variety of human proteins. Bromodomains also bind small molecules that compete with acetyllysine, and therefore bromodomains have been targets for drug discovery efforts. Highly potent and selective ligands with good cellular permeability have been proposed as chemical probes for use in exploring the functions of many of the bromodomain proteins. We report here the discovery of a class of such inhibitors targeting the family VIII bromodomains of SMARCA2 (BRM) and SMARCA4 (BRG1), and PBRM1 (polybromo-1) bromodomain 5. We propose one example from this series, GNE-064, as a chemical probe for the bromodomains SMARCA2, SMARCA4, and PBRM1(5) with the potential for use.
溴结构域是存在于多种人类蛋白质中的乙酰赖氨酸识别结构域。溴结构域还结合与乙酰赖氨酸竞争的小分子，因此溴结构域一直是药物发现努力的目标。具有良好细胞通透性的高活性和选择性配体已被提议用作化学探针，用于探索许多溴结构域蛋白的功能。我们在此报告了一类针对 SMARCA2（BRM）和 SMARCA4（BRG1）家族 VIII 溴结构域以及 PBRM1（多溴-1）溴结构域 5 的抑制剂的发现。我们提出了该系列中的一个例子 GNE-064，作为用于溴结构域 SMARCA2、SMARCA4 和 PBRM1（5）的化学探针，具有潜在的用途。
