Therapeutic targeting of CDK12: a medicinal chemistry perspective.

CDK12 (Cyclin-dependent kinase 12) is a cyclin-dependent kinase that regulates gene transcription by phosphorylating the C-terminal domain of RNA polymerase II, playing a crucial role in maintaining genomic stability. Mutations or alterations in the CDK12 genome can trigger tumorigenesis and progression. Inhibiting the overexpression of CDK12 suppresses tumor growth and proliferation, indicating that it serves both as a biomarker for tumorigenesis and a potential therapeutic target for cancer treatment. In recent years, the structure and biological functions of CDK12 have been progressively elucidated, attracting significant research attention. Currently, the CDK12/13 inhibitor CT7439 is undergoing Phase I/II clinical trials. This paper provides a detailed review of various types of CDK12 small-molecule inhibitors/degraders, primarily based on key structural frameworks. It focuses on exploring the existing structure-activity relationships, aiming to offer a comprehensive perspective for developing highly selective CDK12-targeted inhibitors/degraders and providing valuable insights for future novel drug development.