Discovery of Selective Tertiary Amide Inhibitors of Cyclin-Dependent Kinase 2 (CDK2)
Mingshuo Zeng, Jessica M. Grandner, Marian C. Bryan, Vishal Verma, Robin Larouche‐Gauthier, Jean‐Philippe Leclerc, Liang Zhao, Pouyan Haghshenas, Samuel Aubert‐Nicol, Arun A. Yadav, Melissa Ashley, Jacob Z. Chen, Matthew R. Durk, Karen E. Samy, Marika Nespi, Elizabeth Levy, Karl A. Merrick, John G. Moffat, Jeremy Murray, Angela Oh, Christine Orr, Ehud Segal, Jessica Sims, Christopher J. Sneeringer, Madeleine Prangley, Steffan Vartanian, Steven Magnuson, Brendan T. Parr
Abstract
Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and are frequently altered in cancer cells, thereby leading to uncontrolled proliferation. In this context, CDK2 has emerged as an appealing target for anticancer drug development. Herein, we describe the discovery of a series of selective small molecule inhibitors of CDK2 beginning with historical compounds from our ERK2 program (e.g., compound 6 ). Structure-based drug design led to the potent and selective tool compound 32, where excellent selectivity against ERK2 and CDK4 was achieved by filling the lipophilic DFG-1 pocket and targeting interactions with CDK2-specific lower hinge binding residues, respectively. Compound 32 demonstrated 112% tumor growth inhibition in mice bearing OVCAR3 tumors with 50 mg/kg bis in die (BID) oral dosing.