Discovery of INCB127443: A Potent and Orally Available Inhibitor of Cyclin-Dependent Kinase 2
Ken Mukai, Brandon R. Smith, Qinda Ye, Leslie B. Epling, Chengtsung Lai, Lu Huo, Sean Bowen, Katherine Drake, Keith Kennedy, Jason Boer, Derek Zimmer, Wenliang Zhang, Michael J. Hansbury, Saswati Chand, Jingwei Li, Guofeng Zhang, Kristine Stump, Yvonne Lo, Margaret Favata, Gengjie Yang, Maryanne Covington, Marc C. Deller, Ricardo Macarron, Jeff Jackson, Patrick Mayes, Sunkyu Kim, Xiaozhao Wang, Joshua R. Hummel, Liangxing Wu, Wenqing YaoAbstract
CDK2 is a critical regulator of cell-cycle progression and is an attractive therapeutic target for cancers characterized by dysregulated cyclin E1 signaling. Despite this biological rationale, CDK2 has historically been challenging to target due to the difficulty of achieving selectivity over related CDK isoforms, particularly CDK1, where off-target inhibition may limit the therapeutic window. Building on our previously reported (4-pyrazolyl)-2-aminopyrimidine series, we pursued a multiparameter optimization strategy aimed at improving selectivity for CDK2 over CDK1 while balancing pharmacokinetic and physicochemical properties. Computationally guided replacement of the pyrazole with an imidazole led to a (4-imidazolyl)-2-aminopyrimidine series and culminated in the discovery of INCB127443 (30), a potent and orally bioavailable CDK2 inhibitor. INCB127443 combined favorable selectivity over CDK1 with a relatively flat pharmacokinetic profile, supporting sustained projected CDK2 coverage while limiting potential CDK1 engagement. In vivo, INCB127443 demonstrated dose-dependent inhibition of Rb phosphorylation and antitumor efficacy in CCNE1-high ovarian cancer xenograft models.