2. Academic Validation
  3. Discovery of dCDK9-202 as a Highly Potent and Selective PROTAC CDK9 Degrader with Strong In Vivo Antitumor Activity

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

  • J Med Chem. 2025 Oct 23;68(20):21172-21186. doi: 10.1021/acs.jmedchem.5c01111.
Lin Ma 1,  Long Xie 2,  Yue Wang 2,  Xian Guan 1,  Ying Zhang 2,  Hanjun Guo 2 3 4,  Jiawei Zhou 3 4,  Jiyang Liu 2,  Xingze Huang 2,  Chunyu He 2,  Ye Chen 3 4 5,  Liang Xu 2 5 6,  Xin Han 1 5
Affiliations

Affiliations

  • 1 Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.
  • 2 Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
  • 3 Department of Surgical Oncology, Children's Hospital Zhejiang University School of Medicine, Hangzhou 310052, China.
  • 4 Pediatric Cancer Research Center, National Clinical Research Center for Child Health, Hangzhou 310052, China.
  • 5 Cancer Center of Zhejiang University, Hangzhou 310029, China.
  • 6 Department of Radiation Oncology (Key Laboratory of Cancer Prevention and Intervention China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
PMID: 41066447 DOI: 10.1021/acs.jmedchem.5c01111
Abstract

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 Dmax > 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.

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