Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN). To our surprise, THAL-SNS-032 induced rapid degradation of CDK9 without affecting the levels of other SNS-032 targets. Moreover, the transcriptional changes elicited by THAL-SNS-032 were more like those caused by NVP-2 than those induced by SNS-032. Notably, compound washout did not significantly reduce levels of THAL-SNS-032-induced apoptosis, suggesting that CDK9 degradation had prolonged cytotoxic effects compared with CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation represents a promising strategy for converting multi-targeted inhibitors into selective degraders and reveal that kinase degradation can induce distinct pharmacological effects compared with inhibition.

中文翻译：

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使用选择性 CDK9 抑制或降解对 CDK9 的药理学扰动。

细胞周期蛋白依赖性激酶 9 (CDK9) 是转录延伸的重要调节因子，是癌症治疗的一个有希望的靶点，特别是对于由转录失调驱动的癌症。我们表征了 NVP-2，一种选择性 ATP 竞争性 CDK9 抑制剂，和 THAL-SNS-032，一种选择性 CDK9 降解剂，由与结合 E3 泛素连接酶 Cereblon (CRBN) 的沙利度胺衍生物连接的 CDK 结合 SNS-032 配体组成. 令我们惊讶的是，THAL-SNS-032 诱导 CDK9 快速降解，而不影响其他 SNS-032 目标的水平。此外，由 THAL-SNS-032 引起的转录变化更像是由 NVP-2 引起的，而不是由 SNS-032 引起的。值得注意的是，化合物洗脱并没有显着降低 THAL-SNS-032 诱导的细胞凋亡水平，表明与 CDK9 抑制相比，CDK9 降解具有延长的细胞毒性作用。因此，我们的研究结果表明，沙利度胺偶联是一种将多靶点抑制剂转化为选择性降解剂的有前景的策略，并表明激酶降解与抑制相比可诱导不同的药理作用。