molecules of the month

Context. “Compound 5g” (Incyte) is a selective cyclin-dependent kinase 2 (CDK2) inhibitor. Although CDK2 is a highly pursued cancer drug target, inhibitors targeting the key cell cycle regulator have not enjoyed similar success as CDK4/6 inhibitors, in part due to the major challenge of mitigating off-target CDK1/9 activity through the use of highly selective agents. Given recent data suggesting that resistance to approved CDK4/6 inhibitors may involve a CDK2-mediated compensatory pathway, CDK2 inhibitors may additionally address an unmet need for patients who progress following CDK4/6 therapy. Scaffold hopping on an HTS hit led to “compound 5g” containing the 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one core structure. The compound demonstrated high selectivity (>200x) for CDKs 1/4/6/7/9 and showed submicromolar in vitro activity. Currently, the most advanced…