Discovery of PF-06873600, a CDK2/4/6 Inhibitor for the Treatment of Cancer
Kevin D. Freeman‐Cook, Robert L. Hoffman, Douglas C. Behenna, Britton Boras, Jordan D. Carelli, Wade Diehl, Rose Ann Ferre, You-Ai He, Andrea Hui, Buwen Huang, Nanni Huser, Rhys Jones, Susan E. Kephart, John D. Lapek, Michele McTigue, Nichol Miller, Brion W. Murray, Asako Nagata, Lisa Nguyen, Sherry Niessen, Sacha Ninkovic, Inish O’Doherty, Martha A. Ornelas, James Solowiej, Scott C. Sutton, Khanh Tran, Elaine Tseng, Ravi Visswanathan, Meirong Xu, Luke R. Zehnder, Qin Zhang, Cathy Zhang, Stephen G. Dann
Abstract
Control of the cell cycle through selective pharmacological inhibition of CDK4/6 has proven beneficial in the treatment of breast cancer. Extending this level of control to additional cell cycle CDK isoforms represents an opportunity to expand to additional tumor types and potentially provide benefits to patients that develop tumors resistant to selective CDK4/6 inhibitors. However, broad-spectrum CDK inhibitors have a long history of failure due to safety concerns. In this approach, we describe the use of structure-based drug design and Free–Wilson analysis to optimize a series of CDK2/4/6 inhibitors. Further, we detail the use of molecular dynamics simulations to provide insights into the basis for selectivity against CDK9. Based on overall potency, selectivity, and ADME profile, PF-06873600 (22) was identified as a candidate for the treatment of cancer and advanced to phase 1 clinical trials.