Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310016, PR China; Cancer Center of Zhejiang University, Hangzhou, 310058, PR China; Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
Eur J Med Chem. 2022 Jan 15;228:114012. doi: 10.1016/j.ejmech.2021.114012. Epub 2021 Nov 25.
Cyclin-dependent kinase 12 (CDK12) plays a crucial role in DNA-damage response gene transcription and has recently been validated as a promising target in cancer therapy. However, existing CDK12 inhibitors potently inhibit its closest isoform CDK13, which could cause potential toxicity. Therefore, the development of CDK12 inhibitors with isoform-selectivity against CDK13 continues to be a challenge. By taking advantage of the emerging PROteolysis-TArgeting Chimeras (PROTACs) approach, we have synthesized a potent PROTAC degrader PP-C8 based on the noncovalent dual inhibitors of CDK12/13 and demonstrated its specificity for CDK12 over CDK13. Notably, PP-C8 induces profound degradation of cyclin K simultaneously and downregulates the mRNA level of DNA-damage response genes. Global proteomics profiling revealed PP-C8 is highly selective toward CDK12-cyclin K complex. Importantly, PP-C8 demonstrates profound synergistic antiproliferative effects with PARP inhibitor in triple-negative breast cancer (TNBC). The potent and selective CDK12 PROTAC degrader developed in this study could potentially be used to treat CDK12-dependent cancers as combination therapy.
周期蛋白依赖性激酶 12（CDK12）在 DNA 损伤反应基因转录中发挥着关键作用，最近已被验证为癌症治疗中有前途的靶点。然而，现有的 CDK12 抑制剂强烈抑制其最接近的同工酶 CDK13，这可能会导致潜在的毒性。因此，开发对 CDK13 具有同工酶选择性的 CDK12 抑制剂仍然是一个挑战。利用新兴的 PROteolysis-TArgeting Chimeras（PROTACs）方法，我们基于 CDK12/13 的非共价双重抑制剂合成了一种有效的 PROTAC 降解剂 PP-C8，并证明了其对 CDK12 的特异性高于 CDK13。值得注意的是，PP-C8 可同时诱导细胞周期蛋白 K 的深度降解，并下调 DNA 损伤反应基因的 mRNA 水平。全局蛋白质组学分析显示，PP-C8 对 CDK12-细胞周期蛋白 K 复合物具有高度选择性。重要的是，PP-C8 与 PARP 抑制剂在三阴性乳腺癌（TNBC）中表现出显著的协同抗增殖作用。本研究中开发的有效且选择性的 CDK12 PROTAC 降解剂可作为联合疗法用于治疗 CDK12 依赖性癌症。
