9jk1 | pdb_00009jk1
Crystal structure of CDK12/Cyclin K in complex with covalent inhibitor YJZ5118
Structural highlights
DiseaseCDK12_HUMAN Chromosomal aberrations involving CDK12 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with ERBB2, leading to CDK12-ERBB2 fusion leading to trunctated CDK12 protein not in-frame with ERBB2. FunctionCDK12_HUMAN Cyclin-dependent kinase which displays CTD kinase activity and is required for RNA splicing. Has CTD kinase activity by hyperphosphorylating the C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit RPB1, thereby acting as a key regulator of transcription elongation. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogn inhibitors.[1] [2] [3] Publication Abstract from PubMedCyclin-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 IC(50) 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. Discovery of YJZ5118: A Potent and Highly Selective Irreversible CDK12/13 Inhibitor with Synergistic Effects in Combination with Akt Inhibition.,Yang J, Chang Y, Zhou K, Huang W, Tien JC, Zhang P, Liu W, Zhou L, Zhou Y, Ren X, Mannan R, Mahapatra S, Zhang Y, Hamadeh R, Ervine G, Wang Z, Wang GX, Chinnaiyan AM, Ding K J Med Chem. 2025 Mar 27;68(6):6718-6734. doi: 10.1021/acs.jmedchem.5c00127. Epub , 2025 Mar 13. PMID:40080446[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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