高亲和力SMARCA2/4溴结构域配体的发现以及强效且极具选择性的SMARCA2 PROTAC降解剂的开发。
Discovery of High-Affinity SMARCA2/4 Bromodomain Ligands and Development of Potent and Exceptionally Selective SMARCA2 PROTAC Degraders.
作者信息
Leng Lingying, Tu Wenbin, Yang Lin, Huang Liyue, Wang Mi, Meagher Jennifer L, Chinnaswamy Krishnapriya, Allu Srinivasa Rao, Rej Rohan Kalyan, Tošović Jelena, Harikrishnan Lalgudi, Li Zhenwu, Sui Zhihua, Stuckey Jeanne A, Wang Shaomeng
机构信息
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
出版信息
J Med Chem. 2025 Jan 23;68(2):1113-1133. doi: 10.1021/acs.jmedchem.4c01903. Epub 2025 Jan 2.
In the SWI/SNF chromatin-remodeling complex, the mutually exclusive catalytic ATPase subunits SMARCA2 and SMARCA4 proteins have a synthetic-lethal relationship. Selectively targeting SMARCA2 for degradation is a promising and new therapeutic strategy for human cancers harboring inactivated mutated SMARCA4. In this study, we report the design, synthesis, and biological evaluation of novel SMARCA2/4 ligands and our subsequent design of PROTAC degraders using high-affinity SMARCA ligands and VHL-1 ligands. Our efforts led to the discovery of high-affinity SMARCA2/4 bromodomain ligands and the development of a potent and selective SMARCA2 degrader and a highly potent SMARCA2/4 and PBRM1 degrader.
在SWI/SNF染色质重塑复合物中，相互排斥的催化性ATP酶亚基SMARCA2和SMARCA4蛋白存在合成致死关系。选择性靶向降解SMARCA2是治疗携带失活突变SMARCA4的人类癌症的一种有前景的新治疗策略。在本研究中，我们报告了新型SMARCA2/4配体的设计、合成及生物学评估，以及随后利用高亲和力SMARCA配体和VHL-1配体设计PROTAC降解剂的过程。我们的工作促成了高亲和力SMARCA2/4溴结构域配体的发现，以及一种强效且选择性的SMARCA2降解剂和一种高效的SMARCA2/4及PBRM1降解剂的开发。
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