9JK1

Crystal structure of CDK12/Cyclin K in complex with covalent inhibitor YJZ5118

This is a non-PDB format compatible entry.

Summary for 9JK1

• Entry DOI: 10.2210/pdb9jk1/pdb
• Descriptor: Cyclin-dependent kinase 12, Cyclin-K, 1,2-ETHANEDIOL, ... (7 entities in total)
• Functional Keywords: kinase, covalent inhibitor, selective, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 143760.22

Authors

Huang, W.X.,Zhang, P.J.,Yang, J.Z.,Ding, K. (deposition date: 2024-09-14, release date: 2025-05-07)

Primary citation

Yang, J.,Chang, Y.,Zhou, K.,Huang, W.,Tien, J.C.,Zhang, P.,Liu, W.,Zhou, L.,Zhou, Y.,Ren, X.,Mannan, R.,Mahapatra, S.,Zhang, Y.,Hamadeh, R.,Ervine, G.,Wang, Z.,Wang, G.X.,Chinnaiyan, A.M.,Ding, K.
Discovery of YJZ5118 : A Potent and Highly Selective Irreversible CDK12/13 Inhibitor with Synergistic Effects in Combination with Akt Inhibition.
J.Med.Chem., 68:6718-6734, 2025

PubMed 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 , a novel, potent and highly selective covalent inhibitor of CDK12/13 with reasonable pharmacokinetic profiles. effectively inhibited CDK12 and CDK13 with IC 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, 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, exhibited synergistic effects with Akt inhibitors both in vitro and in vivo.

PubMed: 40080446
DOI: 10.1021/acs.jmedchem.5c00127

Experimental method

X-RAY DIFFRACTION (2.72 Å)