11gv
Crystal structure of selective inhibitor 16 bound at the active site of CDK2
Structural highlights
FunctionCCNA2_HUMAN Essential for the control of the cell cycle at the G1/S (start) and the G2/M (mitosis) transitions. Publication Abstract from PubMedTargeting HR-positive breast cancer via the inhibition of CDK4 and CDK6 has become the standard of care. However, progression inevitably occurs, and emerging data suggest the implication of CDK2 in this resistance mechanism. As part of our efforts to target this resistance, we embarked on a medicinal chemistry campaign to selectively inhibit CDK2 over the broadly essential CDK1. In order to obtain selectivity against CDK1, we utilized a molecular dynamics approach focused on interaction with a conserved lysine in the active site. Additionally, we uncovered a unique mechanism of clearance driven by both metabolism and efflux in rats and demonstrated that we could counter efflux-driven clearance with high permeability. Our efforts resulted in compound 19, which was potent against CDK2, exhibited good selectivity vs CDK4 and CDK1, and had pharmacokinetic properties that enabled evaluation in a CDK2 xenograft model of cancer, where it achieved nearly 80% tumor growth inhibition. Utilizing Molecular Dynamics and Mechanistic Pharmacokinetic Studies in the Design of Selective CDK2 Inhibitors.,Verma VA, Grandner JM, Parr BT, Zeng M, Ashley M, Wang Y, Beroza P, Carione P, Johnson KM, Oh AJ, Murray JM, Kiefer JR, Moffat JG, Prangley M, Merrick K, Vartanian S, Hafner M, Orr CJ, Segal E, Levy ES, Wang J, Xu Z, Wang S, Liu G, Niu Y, Li X, Zhang Q, Ma Z, Sun M, Wu Z, Zhao W, Li Y, Zhang L, Magnuson SR, Samy KE J Med Chem. 2026 Jun 22. doi: 10.1021/acs.jmedchem.5c03803. PMID:42328801[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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