Guo Zhaolin, Wang Peng, Han Yuxuan, Jiang Sisi, Yang Xinyu, Cao Shuang
Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, P. R. China.
Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, P. R. China.
Eur J Med Chem. 2025 Mar 15;286:117319. doi: 10.1016/j.ejmech.2025.117319. Epub 2025 Jan 24.
SMARCA2 is an ATPase that regulates chromatin structure via ATP pathways, controlling cell division and differentiation. SMARCA2's bromodomain and ATPase domain, crucial for chromatin remodeling and cell regulation, are therapeutic targets in cancer treatment. This review explores the role of SMARCA2 in cancer development by studying its protein structure and physiological functions. It further discusses the roles and distinctions of SMARCA2 and its related family proteins in cancer. Additionally, this article categorizes known SMARCA2 inhibitors into four classes based on their basic structure and examines their structure-activity relationships (SAR). This review outlines the structural mechanisms of SMARCA2 inhibitors, highlighting interactions with specific amino acids. By analyzing the SAR of inhibitors, we propose a tailored inhibitor model for the bromodomain of SMARCA2, emphasizing α, γ-H-bond donors/acceptors, and β-rigid structures as crucial for effective binding. This research provides guidance for the design and optimization of future drugs targeting the SMARCA2 protein.
SMARCA2是一种通过ATP途径调节染色质结构的ATP酶，控制细胞分裂和分化。SMARCA2的溴结构域和ATP酶结构域对染色质重塑和细胞调节至关重要，是癌症治疗的靶点。本综述通过研究SMARCA2的蛋白质结构和生理功能，探讨其在癌症发展中的作用。进一步讨论了SMARCA2及其相关家族蛋白在癌症中的作用和区别。此外，本文根据已知的SMARCA2抑制剂的基本结构将其分为四类，并研究它们的构效关系（SAR）。本综述概述了SMARCA2抑制剂的结构机制，突出了与特定氨基酸的相互作用。通过分析抑制剂的SAR，我们提出了一个针对SMARCA2溴结构域的定制抑制剂模型，强调α、γ-H键供体/受体和β刚性结构对有效结合至关重要。本研究为未来靶向SMARCA2蛋白的药物设计和优化提供了指导。
