7KJS

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

7KJS の概要

• エントリーDOI: 10.2210/pdb7kjs/pdb
• 分子名称: 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)
• 機能のキーワード: kinase inhibitor, cell cycle
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 68376.34

構造登録者

McTigue, M.A.,He, Y.,Ferre, R.A. (登録日: 2020-10-26, 公開日: 2021-06-23, 最終更新日: 2024-11-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.187 Å)