2. Academic Validation
  3. Discovery of YJZ5118: A Potent and Highly Selective Irreversible CDK12/13 Inhibitor with Synergistic Effects in Combination with Akt Inhibition

Discovery of YJZ5118: A Potent and Highly Selective Irreversible CDK12/13 Inhibitor with Synergistic Effects in Combination with Akt Inhibition

  • J Med Chem. 2025 Mar 27;68(6):6718-6734. doi: 10.1021/acs.jmedchem.5c00127.
Jianzhang Yang 1 2,  Yu Chang 3,  Kaijie Zhou 1,  Weixue Huang 1,  Jean Ching-Yi Tien 3 4,  Pujuan Zhang 1,  Wenyan Liu 1 3,  Licheng Zhou 2,  Yang Zhou 2,  Xiaomei Ren 1,  Rahul Mannan 3,  Somnath Mahapatra 3,  Yuping Zhang 3,  Rudana Hamadeh 3,  Grafton Ervine 3,  Zhen Wang 1,  George Xiaoju Wang 3 4,  Arul M Chinnaiyan 3 4 5 6 7,  Ke Ding 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Road, Shanghai 200032, China.
  • 2 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou 511400, China.
  • 3 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5 Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 6 Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 7 Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 40080446 DOI: 10.1021/acs.jmedchem.5c00127
Abstract

Cyclin-dependent kinases 12 and 13 (CDK12/13) have emerged as promising therapeutic targets for castration-resistant prostate Cancer (CRPC) and Other human cancers. Despite the development of several CDK12/13 inhibitors, challenges remain in achieving an optimal balance of potency, selectivity and pharmacokinetic properties. Here, we report the discovery of YJZ5118, a novel, potent and highly selective covalent inhibitor of CDK12/13 with reasonable pharmacokinetic profiles. YJZ5118 effectively inhibited CDK12 and CDK13 with IC50 values of 39.5 and 26.4 nM, respectively, while demonstrating high selectivity over Other CDKs. Mass spectrometry analysis, cocrystal structure determination, and pulldown-proteomic experiments confirmed the compound's covalent binding mode with CDK12/13. Functionally, YJZ5118 efficiently suppressed the transcription of DNA damage response genes, induced DNA damage, and triggered Apoptosis. Moreover, the compound significantly inhibited the proliferation of multiple tumor cell lines, particularly prostate Cancer cells. Notably, YJZ5118 exhibited synergistic effects with Akt inhibitors both in vitro and in vivo.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-173273
    CDK12/13 Inhibitor
    CDK