7S85

Crystal structure of CDK2 liganded with compound WN316

Summary for 7S85

• Entry DOI: 10.2210/pdb7s85/pdb
• Descriptor: Cyclin-dependent kinase 2, 1,2-ETHANEDIOL, 2-{[2-(1H-indol-3-yl)ethyl]amino}-5-(trifluoromethoxy)benzoic acid, ... (4 entities in total)
• Functional Keywords: allosteric inhibitor, drug development, cyclin dependent kinase, cell cycle
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 34464.94

Authors

Sun, L.,Schonbrunn, E. (deposition date: 2021-09-17, release date: 2022-09-28, Last modification date: 2023-10-25)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.98 Å)