Discovery of BRD9 Molecular Glue Degraders That Spare Cardiomyocytes

IF 15.6 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Woong Sub Byun, , , Zhe Zhuang, , , Anna P. Hnatiuk, , , Cyrus Jin, , , Zixuan Jiang, , , Kheewoong Baek, , , Evelyn Chao, , , Katherine A. Donovan, , , Eric S. Fischer, , , Mark Mercola, , and , Nathanael S. Gray*, 
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Abstract

Molecular glue degraders (MGDs) represent a class of drug-like small molecules that induce targeted protein degradation (TPD) by promoting selective protein–protein interactions. MGDs offer a promising therapeutic approach by selectively eliminating disease-associated proteins; however, their rational design and discovery have historically remained a significant challenge. The field remains constrained by a lack of strategies to effectively utilize ubiquitin ligases (E3s) for TPD, thus missing the therapeutic potential offered by tissue-specific E3 expression. In this study, we developed ZZ7, a molecular glue degrader that selectively degrades BRD9, a critical component of the SWI/SNF chromatin remodeling complex, specifically in synovial sarcoma cells, while sparing cardiomyocytes. The discovery of ZZ7 was driven by a “chemocentric” approach, incorporating a cysteine-reactive, reversible covalent warhead into a BRD9 inhibitor to transform its function from inhibition to degradation. ZZ7 covalently engages DCAF16 at Cys178, an E3 ligase that is highly expressed in synovial sarcoma cells but relatively underexpressed in human iPSC-derived cardiomyocytes, leveraging a cysteine residue that has not been previously exploited. These findings pave the way for new strategies in tissue- and disease-specific precision therapies, particularly for malignancies characterized by an elevated level of DCAF16 expression.

Abstract Image

发现BRD9分子胶降解剂可保护心肌细胞。
分子胶降解剂(MGDs)是一类类似药物的小分子,通过促进选择性蛋白-蛋白相互作用诱导靶向蛋白降解(TPD)。MGDs通过选择性消除疾病相关蛋白提供了一种很有前景的治疗方法;然而,它们的合理设计和发现在历史上仍然是一个重大挑战。由于缺乏有效利用泛素连接酶(E3)治疗TPD的策略,该领域仍然受到限制,因此错过了组织特异性E3表达提供的治疗潜力。在这项研究中,我们开发了一种分子胶水降解剂ZZ7,它可以选择性地降解BRD9, BRD9是SWI/SNF染色质重塑复合体的关键成分,特别是在滑膜肉瘤细胞中,同时保留心肌细胞。ZZ7的发现是由“化学中心”方法驱动的,将半胱氨酸反应性可逆共价战斗部加入BRD9抑制剂中,将其功能从抑制转变为降解。ZZ7共价结合DCAF16的Cys178, Cys178是一种E3连接酶,在滑膜肉瘤细胞中高度表达,但在人类ipsc衍生的心肌细胞中相对表达不足,利用以前未被利用的半胱氨酸残基。这些发现为组织和疾病特异性精确治疗的新策略铺平了道路,特别是对于以DCAF16表达水平升高为特征的恶性肿瘤。
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来源期刊
CiteScore
24.40
自引率
6.00%
发文量
2398
审稿时长
1.6 months
期刊介绍: The flagship journal of the American Chemical Society, known as the Journal of the American Chemical Society (JACS), has been a prestigious publication since its establishment in 1879. It holds a preeminent position in the field of chemistry and related interdisciplinary sciences. JACS is committed to disseminating cutting-edge research papers, covering a wide range of topics, and encompasses approximately 19,000 pages of Articles, Communications, and Perspectives annually. With a weekly publication frequency, JACS plays a vital role in advancing the field of chemistry by providing essential research.
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