近日，中国科学院上海药物研究所丁宏等研究人员，合作发现一个非保守位点来实现对CECR2的变构共价抑制。2025年1月20日，《中国药理学报》在线发表了这项成果。

研究人员表示，溴结构域（BRD）是一个高度保守的结构模块，为BRD蛋白提供了在调节涉及多种生物过程的蛋白质-蛋白质相互作用中的基本功能，例如染色质介导的基因转录、DNA重组、复制和修复。因此，BRD蛋白的功能失调已被认为与多种人类疾病的发病机制有关。

近年来，科学界在揭示BRD的分子机制和开发靶向这些结构域的抑制剂方面做出了大量努力。尽管这些抑制剂通过竞争结合BRD的乙酰化赖氨酸结合位点来抑制BRD蛋白，但由于这些结合口袋的保守性质，通过竞争性口袋结合来实现BRD蛋白抑制一直是一个挑战。

为了克服这一限制，研究人员通过动态模拟进行了全面分析，识别了CECR2中的一个非保守口袋，从而实现了通过变构调节来抑制BRD家族蛋白。随后，化合物BAY 11-7085在共价对接和体外生物验证后被证明能够共价结合此口袋的C494。通过结构优化化合物LC-CE-7进一步验证了CECR2的变构抑制策略，该化合物是一种具有抗癌效果的变构共价CECR2抑制剂，能够在MDA-MB-231细胞中发挥作用。

附：英文原文

Title: Identifying a non-conserved site for achieving allosteric covalent inhibition of CECR2

Author: Tang, Cai-ling, Li, Yuan-qing, Du, Xi-kun, Fang, Xiao-xia, Guang, Yi-man, Li, Pei-zhuo, Chen, Shuang, Xue, Sheng-yu, Yu, Jia-min, Liu, Xiao-yi, Luo, Yi-pan, Zhou, Lan-xin, Luo, Cheng, Xiong, Huan, Liang, Zhong-jie, Ding, Hong

Issue&Volume: 2025-01-20

Abstract: The bromodomain (BRD) represents a highly conserved structural module that provides BRD proteins with fundamental functionality in modulating protein-protein interactions involved in diverse biological processes such as chromatin-mediated gene transcription, DNA recombination, replication and repair. Consequently, dysregulation of BRD proteins has been implicated in the pathogenesis of numerous human diseases. In recent years, considerable scientific endeavors have focused on unraveling the molecular mechanisms underlying BRDs and developing inhibitors that target these domains. While these inhibitors compete for binding with the acetylated lysine binding site of BRDs, achieving inhibition of BRD proteins via competitive pocket binding has proven challenging due to the conserved nature of these pockets. To address this limitation, the present study employed dynamic simulations for a comprehensive analysis, leading to the identification of a non-conserved pocket in CECR2 for achieving BRD family inhibition through allosteric modulation. Subsequently, the compound BAY 11-7085 was proven capable of covalently binding to C494 of this pocket after covalent docking and biological verification in vitro. The allosteric inhibition strategy of CECR2 was further verified by the structurally optimized compound LC-CE-7, which is an allosteric covalent CECR2 inhibitor with anti-cancer effects in MDA-MB-231 cells.

DOI: 10.1038/s41401-024-01452-z

Source: https://www.nature.com/articles/s41401-024-01452-z