Dinaciclib (DB12021): A Comprehensive Monograph on a Second-Generation, Broad-Spectrum Cyclin-Dependent Kinase Inhibitor

Executive Summary

Dinaciclib (DB12021, SCH 727965) is an investigational, second-generation, small-molecule inhibitor of cyclin-dependent kinases (CDKs) developed by Merck & Co. Structurally classified as a pyrazolo[1,5-a]pyrimidine, Dinaciclib exhibits potent, low-nanomolar inhibitory activity against a specific subset of CDKs, primarily targeting CDK1, CDK2, CDK5, and CDK9. This multi-targeted mechanism of action results in two synergistic antineoplastic effects: the inhibition of cell cycle-related kinases (CDK1, CDK2) induces cell cycle arrest at the G1/S and G2/M transitions, while the inhibition of transcriptional kinases (CDK9) leads to the rapid downregulation of critical anti-apoptotic proteins, most notably Mcl-1, thereby triggering potent apoptosis. This dual mechanism conferred significant and broad antitumor activity across a wide range of preclinical cancer models, including those for leukemia, multiple myeloma, and various solid tumors, where it demonstrated a superior therapeutic index compared to the first-generation pan-CDK inhibitor, flavopiridol.