7S85

Crystal structure of CDK2 liganded with compound WN316

7S85 の概要

• エントリーDOI: 10.2210/pdb7s85/pdb
• 分子名称: Cyclin-dependent kinase 2, 1,2-ETHANEDIOL, 2-{[2-(1H-indol-3-yl)ethyl]amino}-5-(trifluoromethoxy)benzoic acid, ... (4 entities in total)
• 機能のキーワード: allosteric inhibitor, drug development, cyclin dependent kinase, cell cycle
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34464.94

構造登録者

Sun, L.,Schonbrunn, E. (登録日: 2021-09-17, 公開日: 2022-09-28, 最終更新日: 2023-10-25)

主引用文献

Faber, E.B.,Wang, N.,John, K.,Sun, L.,Wong, H.L.,Burban, D.,Francis, R.,Tian, D.,Hong, K.H.,Yang, A.,Wang, L.,Elsaid, M.,Khalid, H.,Levinson, N.M.,Schonbrunn, E.,Hawkinson, J.E.,Georg, G.I.
Screening through Lead Optimization of High Affinity, Allosteric Cyclin-Dependent Kinase 2 (CDK2) Inhibitors as Male Contraceptives That Reduce Sperm Counts in Mice.
J.Med.Chem., 66:1928-1940, 2023

PubMed Abstract: Although cyclin-dependent kinase 2 (CDK2) is a validated target for both cancer and contraception, developing a CDK2 inhibitor with exquisite selectivity has been challenging due to the structural similarity of the ATP-binding site, where most kinase inhibitors bind. We previously discovered an allosteric pocket in CDK2 with the potential to bind a selective compound and then discovered and structurally confirmed an anthranilic acid scaffold that binds this pocket with high affinity. These allosteric inhibitors are selective for CDK2 over structurally similar CDK1 and show contraceptive potential. Herein, we describe the screening and optimization that led to compounds like with nanomolar affinity for CDK2. is metabolically stable, orally bioavailable, and significantly disrupts spermatogenesis, demonstrating this series' therapeutic potential. This work details the discovery of the highest affinity allosteric CDK inhibitors reported and shows promise for this series to yield an efficacious and selective allosteric CDK2 inhibitor.

PubMed: 36701569
DOI: 10.1021/acs.jmedchem.2c01731

実験手法

X-RAY DIFFRACTION (1.98 Å)