CDK12/13和BRD4分子胶降解剂的合理设计。

Nathanael Schiander Gray, Zhe Zhuang, Woong Sub Byun, Zuzanna Kozicka, Katherine Donovan, Brendan Dwyer, Abby Thornhill, Hannah Jones, Zixuan Jiang, Xijun Zhu, Eric Fischer, Nicolas Thomä
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引用次数: 0

摘要

靶向蛋白降解(TPD)是一种新兴的选择性消除疾病相关蛋白的治疗方法。虽然分子胶降解剂表现出类似药物的特性,但它们的发现传统上是偶然的,往往需要事后的合理化。在这项研究中,我们展示了合理的,机制指导设计的分子胶水降解剂使用粘合部分。基于既定的原理,通过在几个小分子抑制剂上附加化学粘合片段,我们成功地将它们转化为降解剂,从而避免了对特定E3泛素连接酶招募者的需要。具体来说,我们发现将疏水芳香环或双键结合到周期蛋白依赖性激酶12和13 (CDK12/13)双抑制剂中,可以招募DNA损伤结合蛋白1 (DDB1),从而将高分子量二价CDK12降解物转化为有效的单价CDK12/13分子胶降解物。我们还展示了通过招募DDB1和CUL4相关因子16 (DCAF16) E3连接酶,将半胱氨酸反应性战斗部连接到含溴结构域蛋白4 (BRD4)抑制剂上,将其转化为降解剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders.

Targeted protein degradation (TPD) is an emerging therapeutic approach for the selective elimination of disease-related proteins. While molecular glue degraders exhibit drug-like properties, their discovery has traditionally been serendipitous and often requires post-hoc rationalization. In this study, we demonstrate the rational, mechanism-guided design of molecular glue degraders using gluing moieties. Building on established principles, by appending a chemical gluing moiety to several small molecule inhibitors, we successfully transformed them into degraders, obviating the need for a specific E3 ubiquitin ligase recruiter. Specifically, we found that incorporating a hydrophobic aromatic ring or a double bond into a cyclin-dependent kinase 12 and 13 (CDK12/13) dual inhibitor enabled the recruitment of DNA damage-binding protein 1 (DDB1), thereby transforming a high-molecular-weight bivalent CDK12 degrader into a potent monovalent CDK12/13 molecular glue degrader. We also showcase that attaching a cysteine-reactive warhead to a bromodomain-containing protein 4 (BRD4) inhibitor converts it into a degrader by recruiting the DDB1 and CUL4 associated factor 16 (DCAF16) E3 ligase.

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