7KJS

Crystal structure of CDK2/cyclin E in complex with PF-06873600

Summary for 7KJS

• Entry DOI: 10.2210/pdb7kjs/pdb
• Descriptor: Cyclin-dependent kinase 2, G1/S-specific cyclin-E1, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one, ... (4 entities in total)
• Functional Keywords: kinase inhibitor, cell cycle
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 68376.34

Authors

McTigue, M.A.,He, Y.,Ferre, R.A. (deposition date: 2020-10-26, release date: 2021-06-23, Last modification date: 2024-11-20)

Primary citation

Freeman-Cook, K.D.,Hoffman, R.L.,Behenna, D.C.,Boras, B.,Carelli, J.,Diehl, W.,Ferre, R.A.,He, Y.A.,Hui, A.,Huang, B.,Huser, N.,Jones, R.,Kephart, S.E.,Lapek, J.,McTigue, M.,Miller, N.,Murray, B.W.,Nagata, A.,Nguyen, L.,Niessen, S.,Ninkovic, S.,O'Doherty, I.,Ornelas, M.A.,Solowiej, J.,Sutton, S.C.,Tran, K.,Tseng, E.,Visswanathan, R.,Xu, M.,Zehnder, L.,Zhang, Q.,Zhang, C.,Dann, S.
Discovery of PF-06873600, a CDK2/4/6 Inhibitor for the Treatment of Cancer.
J.Med.Chem., 64:9056-9077, 2021

PubMed 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 () was identified as a candidate for the treatment of cancer and advanced to phase 1 clinical trials.

PubMed: 34110834
DOI: 10.1021/acs.jmedchem.1c00159

Experimental method

X-RAY DIFFRACTION (2.187 Å)