9GOP

Crystal structure of CDK2-cyclin E1 bound by compound 30

This is a non-PDB format compatible entry.

Summary for 9GOP

• Entry DOI: 10.2210/pdb9gop/pdb
• Descriptor: Cyclin-dependent kinase 2, G1/S-specific cyclin-E1, 2-[(2~{S})-1-[9-ethyl-6-[(2-methyl-5-methylsulfonyl-pyrazol-3-yl)amino]purin-2-yl]-4,4-bis(fluoranyl)pyrrolidin-2-yl]propan-2-ol, ... (4 entities in total)
• Functional Keywords: kinase, cdk2, inhibitor, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 67514.51

Authors

Collie, G.W. (deposition date: 2024-09-05, release date: 2025-09-10, Last modification date: 2025-09-24)

Primary citation

Ghosh, A.,Ahmed, A.,Amoiradaki, K.,Balazs, A.Y.S.,Barlaam, B.,Bodnarchuk, M.S.,Collie, G.W.,Dale, I.L.,Denz, C.R.,Drew, L.,Edmondson, S.D.,Fan, J.,Fawell, S.,Goldberg, F.W.,Gopalsamy, A.,Grondine, M.,Guo, G.,Hande, S.M.,Hatoum-Mokdad, H.,Hird, A.W.,Howells, R.,Hao-Ru Hsu, J.,Hudson, J.,Jackson, A.,Lamb, M.L.,Lamont, G.M.,Lamont, S.,Lichtor, P.A.,McWilliams, L.,Milne, D.,Mlynarski, S.N.,Narasimhan, P.,Peters, M.F.,Pflug, A.,Pollard, H.K.,Qin, M.,Reimer, C.,Robbins, K.J.,Robinson, J.,Sha, L.,She, H.,Sheppeck 2nd, J.E.,Singh, B.,Song, K.,Su, Q.,Telmesani, R.,Throner, S.,Vasalou, C.,Wang, L.,Wang, Y.,Wilson, D.M.,Winlow, P.,Yang, W.,Yao, T.,Zhang, Y.,Zhang, Z.,Zindel, D.,Johannes, J.W.
Discovery of AZD8421: A Potent CDK2 Inhibitor with Selectivity Against Other CDK Family Members and the Human Kinome.
J.Med.Chem., 68:18164-18177, 2025

PubMed Abstract: Targeting CDK2 with first generation CDK2 inhibitors suffered from a reduced therapeutic index likely due to toxicity stemming from lack of selectivity against the CDK family and other kinases. Recently, CDK2 has been identified as a mediator of resistance to CDK4/6 inhibitors in the context of high levels of cyclin E expression. Discovery of highly selective CDK2 inhibitors may minimize off-target effects, reduce toxicity observed with first generation CDK2 inhibitors, and allow precise targeting of aberrant cell cycle progression and resistance mechanisms mediated by high cyclin E/CDK2 activity. To this end, we report the discovery of AZD8421, a potent and highly selective CDK2 inhibitor, which exhibits superior selectivity for CDK2 over CDK1, other CDK family members, and the broader human kinome. AZD8421 demonstrates favorable pharmacokinetic properties, including excellent solubility and robust in vitro stability. Demonstrated efficacy in an ovarian cancer patient-derived xenograft model further supports its potential as a therapeutic agent.

PubMed: 40899577
DOI: 10.1021/acs.jmedchem.5c01478

Experimental method

X-RAY DIFFRACTION (2.158 Å)