Pompom Ghosh, Maximilian Schmitz, Thiyagamurthy Pandurangan, Solomon Tadesse Zeleke, Sean Chin Chan, John Mosior, Luxin Sun, Vinayak Palve, Dylan Grassie, Kanchan Anand, Sylvia Frydman, William R Roush, Ernst Schönbrunn, Matthias Geyer, Derek Duckett, Andrii Monastyrskyi
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引用次数: 0
摘要
CDK12 抑制剂 SR-4835 能促进细胞周期蛋白 K 的蛋白酶体降解,这取决于 CDK12 和 CUL4-RBX1-DDB1 E3 连接酶复合物的存在。该抑制剂具有分子胶合活性,这与其抑制细胞生长的能力增强有关。这种效果是通过促进形成需要小分子 SR-4835、CDK12 和适配蛋白 DDB1 的三元复合物来实现的,从而导致随后的泛素化和细胞周期蛋白 K 降解。我们成功地解决了三元复合物的结构,从而能够从头开始设计分子胶,将四种不同的 CDK12 支架抑制剂(包括临床泛 CDK 抑制剂 dinaciclib)转化为细胞周期蛋白 K 降解剂。这些研究成果不仅加深了我们对CDK12在细胞调控中作用的理解,而且突显了在设计分子粘合剂以靶向降解与细胞周期蛋白K活性失调有关的癌症蛋白质方面取得的重大进展。
Discovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K.
The CDK12 inhibitor SR-4835 promotes the proteasomal degradation of cyclin K, contingent on the presence of CDK12 and the CUL4-RBX1-DDB1 E3 ligase complex. The inhibitor displays molecular glue activity, which correlates with its enhanced ability to inhibit cell growth. This effect is achieved by facilitating the formation of a ternary complex that requires the small molecule SR-4835, CDK12, and the adaptor protein DDB1, leading to the subsequent ubiquitination and degradation of cyclin K. We have successfully solved the structure of the ternary complex, enabling the de novo design of molecular glues that transform four different CDK12 scaffold inhibitors, including the clinical pan-CDK inhibitor dinaciclib, into cyclin K degraders. These results not only deepen our understanding of CDK12's role in cell regulation but also underscore significant progress in designing molecular glues for targeted protein degradation in cancers associated with dysregulated cyclin K activity.