2. Academic Validation
  3. Discovery of Potent and Selective CDK9 Degraders for Targeting Transcription Regulation in Triple-Negative Breast Cancer

Discovery of Potent and Selective CDK9 Degraders for Targeting Transcription Regulation in Triple-Negative Breast Cancer

  • J Med Chem. 2021 Oct 14;64(19):14822-14847. doi: 10.1021/acs.jmedchem.1c01350.
Dan Wei 1 2,  Hanlin Wang 3 4 2,  Qinghe Zeng 1 2,  Wenjing Wang 1 2,  Bingbing Hao 4,  Xule Feng 1,  Peipei Wang 4,  Ning Song 4 2,  Weijuan Kan 4,  Guifang Huang 5,  Xiaoyu Zhou 1,  Minjia Tan 4,  Yubo Zhou 4 2 6,  Ruimin Huang 1 2 5,  Jia Li 3 4 2 6 7,  Xiao-Hua Chen 1 2 7
Affiliations

Affiliations

  • 1 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 College of Pharmacy, Fudan University, Shanghai 201203, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 6 Zhongshan Institute for Drug Discovery, The Institutes of Drug Discovery and Development, CAS, Zhongshan, Guangdong 528400, China.
  • 7 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
PMID: 34538051 DOI: 10.1021/acs.jmedchem.1c01350
Abstract

Triple-negative breast Cancer (TNBC) is highly aggressive with very limited treatment options due to the lack of efficient targeted therapies and thus still remains clinically challenging. Targeting transcription-associated cyclin-dependent kinases to remodel transcriptional regulation shows great promise in Cancer therapy. Herein, we report the synthesis, optimization, and evaluation of new series of heterobifunctional molecules as highly selective and efficacious CDK9 degraders, enabling potent inhibition of TNBC cell growth and rapidly targeted degradation of CDK9. Moreover, the most potent CDK9 degrader (compound 45) induces cell Apoptosis in vitro and inhibits tumor growth in the MDA-MB-231 TNBC model. Furthermore, the RNA-seq, immunohistochemistry assays demonstrate that the CDK9 degrader downregulates the downstream targets, such as MYC, at the transcriptional level, resulting Apoptosis in TNBC cells. Our work establishes that 45 is a highly potent and efficacious CDK9 degrader for targeting transcription regulation, which represents an effective strategy and great potential as a new targeted therapy for TNBC.

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