Discovery of (4-Pyrazolyl)-2-aminopyrimidines as Potent and Selective Inhibitors of Cyclin-Dependent Kinase 2 PMID: 38325398

Target-related Cytokines

2026-09-23

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

J Med Chem. 2024 Feb 22;67(4):3112-3126. doi: 10.1021/acs.jmedchem.3c02287.

Joshua R Hummel ¹ , Kai-Jiong Xiao ¹ , Jeffrey C Yang ¹ , Leslie B Epling ¹ , Ken Mukai ¹ , Qinda Ye ¹ , Meizhong Xu ¹ , Dingquan Qian ¹ , Lu Huo ¹ , Michael Weber ¹ , Valerie Roman ¹ , Yvonne Lo ¹ , Katherine Drake ¹ , Kristine Stump ¹ , Maryanne Covington ¹ , Kanishk Kapilashrami ¹ , Guofeng Zhang ¹ , Min Ye ¹ , Sharon Diamond ¹ , Swamy Yeleswaram ¹ , Ricardo Macarron ¹ , Marc C Deller ¹ , Susan Wee ¹ , Sunkyu Kim ¹ , Xiaozhao Wang ¹ , Liangxing Wu ¹ , Wenqing Yao ¹

Affiliations

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 17, a kinase selective and highly potent CDK2 Inhibitor (IC₅₀ = 0.29 nM). The evaluation of 17 in CCNE1-amplified mouse models shows the pharmacodynamic inhibition of CDK2, measured by reduced Rb phosphorylation, and antitumor activity.