9NYR

Cryo-EM structure of CDK2/CyclinE1 in complex with CRBN/DDB1 and Cpd 24

This is a non-PDB format compatible entry.

Summary for 9NYR

• Entry DOI: 10.2210/pdb9nyr/pdb
• EMDB information: 49942
• Descriptor: Cyclin-dependent kinase 2, G1/S-specific cyclin-E1, DNA damage-binding protein 1, ... (6 entities in total)
• Functional Keywords: kinase, degrader, cdk2, cyclin e, cell cycle, crbn
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 242712.78

Authors

Collier, P.,Zheng, X.,Ford, M.,Weiss, M.,Aversa, R.,Chen, D.,Li, K.,Growney, J.D.,Yang, A.,Sathappa, M.,Breitkopf, S.B.,Enerson, B.,Sawant, R.,Su, L.,Howarth, L.,Liang, T.,Paul, A.,Sharma, K.,Williams, J.,Kwiatkowski, N.P. (deposition date: 2025-03-28, release date: 2026-02-04)

Primary citation

Collier, P.N.,Zheng, X.,Ford, M.,Weiss, M.,Chen, D.,Li, K.,Growney, J.D.,Yang, A.,Sathappa, M.,Breitkopf, S.B.,Enerson, B.,Liang, T.,Paul, A.,Sawant, R.,Su, L.,Aversa, R.J.,Howarth, C.,Sharma, K.,Williams, J.,Kwiatkowski, N.P.
Discovery of Selective and Orally Bioavailable Heterobifunctional Degraders of Cyclin-Dependent Kinase 2.
J.Med.Chem., 68:18407-18422, 2025

PubMed Abstract: Cyclin-dependent kinase 2 (CDK2) plays an important role in cell cycle regulation and has emerged as a compelling target for the treatment of cancer, largely because of its potential to overcome the resistance associated with CDK4/6 inhibition. Efforts to develop CDK2 inhibitors have historically proven challenging due to undesirable safety profiles associated with inhibiting off-target CDK isoforms. Herein, we describe the structure-guided discovery of a series of orally bioavailable and selective degraders of CDK2. Degrader demonstrated improved phenotypic selectivity compared to a clinical CDK2 inhibitor, with greater specificity for disease-relevant cyclin E1 (CCNE1)-amplified cancer cells vs nonamplified cohort. The antitumor activity of in mice bearing CCNE1-amplified HCC1569 tumors correlated with sustained >90% degradation of CDK2 and sustained 90% inhibition of Rb phosphorylation.

PubMed: 40833690
DOI: 10.1021/acs.jmedchem.5c01160

Experimental method

ELECTRON MICROSCOPY (3.9 Å)