8H6T

Complex structure of CDK2/Cyclin E1 and a potent, selective small molecule inhibitor

Summary for 8H6T

• Entry DOI: 10.2210/pdb8h6t/pdb
• Related: 8H6O 8H6P
• Descriptor: Cyclin-dependent kinase 2, G1/S-specific cyclin-E1, (1R,3S)-3-{3-[(pyridin-2-yl)amino]-1H-pyrazol-5-yl}cyclopentyl propan-2-ylcarbamate, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, selective, anti-tumor, cell cycle
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 66082.70

Authors

Ren, X. (deposition date: 2022-10-18, release date: 2023-02-22, Last modification date: 2024-11-20)

Primary citation

Yu, Y.,Huang, J.,He, H.,Han, J.,Ye, G.,Xu, T.,Sun, X.,Chen, X.,Ren, X.,Li, C.,Li, H.,Huang, W.,Liu, Y.,Wang, X.,Gao, Y.,Cheng, N.,Guo, N.,Chen, X.,Feng, J.,Hua, Y.,Liu, C.,Zhu, G.,Xie, Z.,Yao, L.,Zhong, W.,Chen, X.,Liu, W.,Li, H.
Accelerated Discovery of Macrocyclic CDK2 Inhibitor QR-6401 by Generative Models and Structure-Based Drug Design.
Acs Med.Chem.Lett., 14:297-304, 2023

PubMed Abstract: Selective CDK2 inhibitors have the potential to provide effective therapeutics for CDK2-dependent cancers and for combating drug resistance due to high cyclin E1 (CCNE1) expression intrinsically or CCNE1 amplification induced by treatment of CDK4/6 inhibitors. Generative models that take advantage of deep learning are being increasingly integrated into early drug discovery for hit identification and lead optimization. Here we report the discovery of a highly potent and selective macrocyclic CDK2 inhibitor QR-6401 () accelerated by the application of generative models and structure-based drug design (SBDD). QR-6401 () demonstrated robust antitumor efficacy in an OVCAR3 ovarian cancer xenograft model via oral administration.

PubMed: 36923916
DOI: 10.1021/acsmedchemlett.2c00515

Experimental method

X-RAY DIFFRACTION (3 Å)