8UV0

Discovery of (4-Pyrazolyl)-2-Aminopyrimidines as Potent and Selective Inhibitors of Cyclin-Dependent Kinase 2

Summary for 8UV0

• Entry DOI: 10.2210/pdb8uv0/pdb
• Descriptor: Cyclin-dependent kinase 2, 1-{(4M)-4-[2-{[1-(cyclopropanesulfonyl)piperidin-4-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrazol-1-yl}-2-methylpropan-2-ol (3 entities in total)
• Functional Keywords: cdk2, serine/threonine kinase, cell cycle regulation, aminopyrimidine, inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34333.82

Authors

Deller, M.C.,Epling, L.B. (deposition date: 2023-11-02, release date: 2024-02-14, Last modification date: 2024-03-06)

Primary citation

Hummel, J.R.,Xiao, K.J.,Yang, J.C.,Epling, L.B.,Mukai, K.,Ye, Q.,Xu, M.,Qian, D.,Huo, L.,Weber, M.,Roman, V.,Lo, Y.,Drake, K.,Stump, K.,Covington, M.,Kapilashrami, K.,Zhang, G.,Ye, M.,Diamond, S.,Yeleswaram, S.,Macarron, R.,Deller, M.C.,Wee, S.,Kim, S.,Wang, X.,Wu, L.,Yao, W.
Discovery of (4-Pyrazolyl)-2-aminopyrimidines as Potent and Selective Inhibitors of Cyclin-Dependent Kinase 2.
J.Med.Chem., 67:3112-3126, 2024

PubMed Abstract: CDK2 is a critical regulator of the cell cycle. For a variety of human cancers, the dysregulation of CDK2/cyclin E1 can lead to tumor growth and proliferation. Historically, early efforts to develop CDK2 inhibitors with clinical applications proved unsuccessful due to challenges in achieving selectivity over off-target CDK isoforms with associated toxicity. In this report, we describe the discovery of (4-pyrazolyl)-2-aminopyrimidines as a potent class of CDK2 inhibitors that display selectivity over CDKs 1, 4, 6, 7, and 9. SAR studies led to the identification of compound , a kinase selective and highly potent CDK2 inhibitor (IC = 0.29 nM). The evaluation of in -amplified mouse models shows the pharmacodynamic inhibition of CDK2, measured by reduced Rb phosphorylation, and antitumor activity.

PubMed: 38325398
DOI: 10.1021/acs.jmedchem.3c02287

Experimental method

X-RAY DIFFRACTION (1.55 Å)