THZ531

THZ531 is a first-in-class, irreversible covalent inhibitor of cyclin-dependent kinase 12 (CDK12) and cyclin-dependent kinase 13 (CDK13). It exhibits high selectivity for CDK12 (IC50 158 nM) and CDK13 (IC50 69 nM) over other cyclin-dependent kinases. THZ531 acts by binding to a cysteine residue in the kinase active site, resulting in inhibition of transcriptional elongation, splicing, and 3′-end RNA processing, leading to reduced expression of key oncogenic and DNA damage response genes. In preclinical studies, THZ531 demonstrates anti-proliferative and pro-apoptotic effects, notably in cancer cell lines including lymphomas, multiple myeloma, colorectal cancer, breast cancer (especially triple-negative), and ovarian cancer. It is under investigation for its ability to sensitize cancer cells to other agents and overcome resistance to standard chemotherapies.