ISM6466A

ISM6466A is a novel, covalent small-molecule inhibitor of cyclin-dependent kinase 12 (CDK12) developed by Insilico Medicine. CDK12, in complex with cyclin K, regulates the elongation step of RNA transcription by phosphorylating Ser2 on the carboxy-terminal domain (CTD) of RNA polymerase II. By inhibiting CDK12, ISM6466A selectively downregulates the expression of genes involved in the DNA Damage Response (DDR), such as BRCA1, BRCA2, and ATR. Preclinical studies have demonstrated significant anti-tumor efficacy in models of triple-negative breast cancer (TNBC) and acute myeloid leukemia (AML), showing favorable ADME properties and a reasonable safety profile in early toxicology assessments.