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

Discovery of Orally Bioavailable and Potent CDK9 Inhibitors for Targeting Transcription Regulation in Triple-Negative Breast Cancer

  • J Med Chem. 2024 Jun 27;67(12):10035-10056. doi: 10.1021/acs.jmedchem.4c00233.
Wen-Jing Wang 1 2,  Lixin Gao 3 4,  Simei Wang 5 2,  Wensi Huang 5 2,  Xin-Yu Meng 1 2,  Hao Hu 1,  Ziqiang Chen 5 2,  Jingya Sun 5,  Yali Yuan 6,  Yubo Zhou 3 2 7,  Xingxing Diao 5 2,  Ruimin Huang 5 2,  Jia Li 2 6 7 8 9 10,  Xiao-Hua Chen 1 2 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China.
  • 5 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 6 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 7 Zhongshan Institute for Drug Discovery, The Institutes of Drug Discovery and Development, CAS, Zhongshan 528400, China.
  • 8 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 9 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 10 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
PMID: 38885173 DOI: 10.1021/acs.jmedchem.4c00233
Abstract

Triple-negative breast Cancer (TNBC) represents a highly aggressive and heterogeneous malignancy. Currently, effective therapies for TNBC are very limited and remain a significant unmet clinical need. Targeting the transcription-regulating cyclin-dependent kinase 9 (CDK9) has emerged as a promising avenue for therapeutic treatment of TNBC. Herein, we report the design, synthesis, optimization, and evaluation of a new series of aminopyrazolotriazine compounds as orally bioavailable, potent, and CDK9/2 selectivity-improved inhibitors, enabling efficacious inhibition of TNBC cell growth, as well as notable antitumor effect in TNBC models. The compound C35 demonstrated low-nanomolar potency with substantially improved CDK9/2 selectivity, downregulated the CDK9-downstream targets (e.g., Mcl-1), and induced Apoptosis in TNBC cell lines. Moreover, with the desired oral bioavailability, oral administration of C35 could significantly suppress the tumor progression in two TNBC mouse models. This study demonstrates that target transcriptional regulation is an effective strategy and holds promising potential as a targeted therapy for the treatment of TNBC.

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