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

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.细胞周期蛋白依赖性激酶12和13（Cyclin-dependent kinases 12 and 13，CDK12/13）已成为去势抵抗性前列腺癌（castration-resistant prostate cancer，CRPC）及其他人类恶性肿瘤的极具潜力的治疗靶点。尽管已有多款CDK12/13抑制剂被开发出来，但在实现效价、选择性与药代动力学特性的最优平衡方面仍存在诸多挑战。本研究报道了YJZ5118的发现：这是一种新型、强效且高选择性的CDK12/13共价抑制剂，具备良好的药代动力学特性。YJZ5118可有效抑制CDK12与CDK13的活性，其半数抑制浓度（IC50）分别为39.5 nM与26.4 nM，同时对其他细胞周期蛋白依赖性激酶家族成员展现出优异的选择性。质谱分析、共晶结构解析以及下拉蛋白质组学实验证实，该化合物可通过共价结合模式与CDK12/13相结合。功能层面上，YJZ5118可高效抑制DNA损伤应答基因的转录，诱导DNA损伤并触发细胞凋亡。此外，该化合物可显著抑制多种肿瘤细胞系的增殖，尤以前列腺癌细胞为甚。值得注意的是，YJZ5118在体外与体内环境中均与Akt抑制剂展现出协同作用。