Discovery of dCDK9-202 as a Highly Potent and Selective PROTAC CDK9 Degrader with Strong <i>In Vivo</i> Antitumor Activity

As a promising cancer therapeutic target, the development of highly efficient and selective small-molecule drugs targeting CDK9 remains a significant challenge due to the similarity of its ATP-binding site to that of other CDKs. Here, we report our design, synthesis, and evaluation of CDK9 degraders with high selectivity based upon the concept of PROTAC. The representative compound dCDK9-202 demonstrates a DC₅₀ value of 3.5 nM and <i>D</i>_max > 99% in inducing rapid CDK9 degradation in the TC-71 cell line. Notably, dCDK9-202 achieves significant cell growth inhibition with an IC₅₀ value of 8.5 nM in the TC-71 cell line and also low nanomolar IC₅₀ values in multiple cancer cell lines originating from the lung, liver, bone, and brain. Moreover, intravenous administration of dCDK9-202 effectively inhibits TC-71 tumor growth without any signs of toxicity in mice. This promising CDK9 degrader dCDK9-202 has a high potential for advanced preclinical development in the treatment of CDK9-addicted human cancers.