Discovery and preclinical evaluation of ZLC853 as a potential clinical candidate covalently targeting CDK12/13 kinases
4 affiliations
- 1State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
- 2Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA
- 3National Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China
- 4International 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, Guangzhou 511400, China
Abstract
Previous studies highlight the therapeutic promise of inhibiting cyclin-dependent kinases 12 and 13 (CDK12/13) for castration-resistant prostate cancer (CRPC) and other malignancies. However, developing small molecule modulators of CDK12/13 that exhibit an optimal combination of potency, selectivity and favorable pharmacokinetics (PK) remains challenging. In this study, we present ZLC853, a potent, selective, and orally bioavailable covalent inhibitor of CDK12/13 developed through PK-oriented optimization of our previously reported inhibitor YJZ5118. ZLC853 potently inhibited CDK12 and CDK13 with IC50 values of 40.0 and 18.2 nmol/L, respectively, and displayed exceptional kinase selectivity in a comprehensive KinomeScan assay. Its covalent binding mechanism was unequivocally validated through mass spectrometry, co-crystal structure analysis, cellular pull-down assays, and washout experiments. Functionally, ZLC853 suppressed the transcription of DNA damage response genes, induced DNA damage, and promoted apoptosis. Additionally, ZLC853 exhibited good oral bioavailability and robust antitumor activity across multiple prostate cancer models, both in vitro and in vivo, supporting it as a promising candidate for clinical investigation.
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BibTeX
@article{zhou2026discovery,
title = {{Discovery and preclinical evaluation of ZLC853 as a potential clinical candidate covalently targeting CDK12/13 kinases}},
author = {Kaijie Zhou and Licheng Zhou and Jean C. Tien and Weixue Huang and Wenyan Liu and Xinyu Sun and Bohai Fan and Xin Huang and Jun Wang and Yu Chang and Jianzhang Yang and Yue Yin and Chen Su and Qingrun Li and Rahul Mannan and Somnath Mahapatra and Yunhui Cheng and Abigail J. Todd and Christina E. Wheeler and Shuqin Li and Yang Zhou and Xiaomei Ren and George Xiaoju Wang and Zhen Wang and Arul M. Chinnaiyan and Ke Ding},
journal = {Acta pharmaceutica Sinica. B},
year = {2026},
month = jul,
doi = {10.1016/j.apsb.2026.07.041},
url = {https://europepmc.org/article/PMC/PMC13729719},
note = {CC BY},
}
RIS
TY - JOUR
TI - Discovery and preclinical evaluation of ZLC853 as a potential clinical candidate covalently targeting CDK12/13 kinases
AU - Kaijie Zhou
AU - Licheng Zhou
AU - Jean C. Tien
AU - Weixue Huang
AU - Wenyan Liu
AU - Xinyu Sun
AU - Bohai Fan
AU - Xin Huang
AU - Jun Wang
AU - Yu Chang
AU - Jianzhang Yang
AU - Yue Yin
AU - Chen Su
AU - Qingrun Li
AU - Rahul Mannan
AU - Somnath Mahapatra
AU - Yunhui Cheng
AU - Abigail J. Todd
AU - Christina E. Wheeler
AU - Shuqin Li
AU - Yang Zhou
AU - Xiaomei Ren
AU - George Xiaoju Wang
AU - Zhen Wang
AU - Arul M. Chinnaiyan
AU - Ke Ding
PY - 2026
DA - 2026/07/29
JO - Acta pharmaceutica Sinica. B
DO - 10.1016/j.apsb.2026.07.041
UR - https://europepmc.org/article/PMC/PMC13729719
AB - Previous studies highlight the therapeutic promise of inhibiting cyclin-dependent kinases 12 and 13 (CDK12/13) for castration-resistant prostate cancer (CRPC) and other malignancies. However, developing small molecule modulators of CDK12/13 that exhibit an optimal combination of potency, selectivity and favorable pharmacokinetics (PK) remains challenging. In this study, we present ZLC853, a potent, selective, and orally bioavailable covalent inhibitor of CDK12/13 developed through PK-oriented optimization of our previously reported inhibitor YJZ5118. ZLC853 potently inhibited CDK12 and CDK13 with IC50 values of 40.0 and 18.2 nmol/L, respectively, and displayed exceptional kinase selectivity in a comprehensive KinomeScan assay. Its covalent binding mechanism was unequivocally validated through mass spectrometry, co-crystal structure analysis, cellular pull-down assays, and washout experiments. Functionally, ZLC853 suppressed the transcription of DNA damage response genes, induced DNA damage, and promoted apoptosis. Additionally, ZLC853 exhibited good oral bioavailability and robust antitumor activity across multiple prostate cancer models, both in vitro and in vivo, supporting it as a promising candidate for clinical investigation.
SN - 2211-3835
SN - 2211-3843
ER -