Discovery of INCB123667, a potent and selective cyclin-dependent kinase 2 (CDK2) inhibitor for the treatment of cyclin E dysregulated cancers

Background: Dysregulation of the CDK/cyclin complex causes aberrant cell cycle entry and progression that can lead to cancer. For instance, CDK2/ cyclin E governs G1-S transition overexpression has been associated with ovarian breast cancers. Our initial studies have demonstrated genetic depletion CDK2 inhibits growth survival in cancer cells overexpressing E. Furthermore, inhibition may be effective cancers resistant clinically approved CDK4/6 therapies as increased CDK2/cyclin activity reported a compensatory mechanism. Current inhibitors are limited by off-target on other CDK family members, including CDK1. Here we report identification characterization INCB123667, potent selective, orally available small molecule inhibitor CDK2, for treatment high unmet medical need, such E-amplified tumors. Materials methods: Biochemical cell-based assays were used determine potency selectivity INCB123667. Additionally, antitumor was assessed E-overexpressing lines, tumor xenograft models. Results: In biochemical assays, INCB123667 sub-nanomolar not active against CDK1, CDK4, CDK6, CDK7, CDK9. Selectivity confirmed across an extended panel kinases, G protein-coupled receptors, ion channels, transporters. studies, inhibited phosphorylation retinoblastoma (Rb), substrate key regulator transition. Consistent its overall profile, expression regulatory genes E-overexpressed cells. transcriptional gene signature distinct from inhibitors. cellular addition resulted G1 arrest senescence. OVCAR3 model, which harbors amplification, Rb dose-dependent along minimal body weight loss. IGROV-1 is amplified, same doses less blocking inhibiting growth. Notably, vitro vivo more sensitive compared normal levels Conclusions: data indicate selective kinase These preclinical findings support ongoing clinical evaluation CDK2-selective Conflict interest: Ownership: Susan Wee, Yvonne Lo, Michael Hansbury, Weber, Valerie Roman, Lu Huo, Katherine Drake, Kristine Stump, Jie Yang, Saswati Chand, Cynthia Timmers, Joshua Hummel, Guofeng Zhang, Yan-ou Maryanne Covington, Sunkyu Kim: Employment stock ownership – Incyte Corporation. Min Ye, Niu Shin, Hollie Skaggs, Kanishk Kapilashrami, Yingda Liangxing Wu, Holly Koblish: Former employee