Abstract 5991: Development and characterization of a novel CDK4/6 inhibitor for the treatment of CDK4/6 dependent cancers

Abstract

CDK4/6 inhibitors give clinical benefit in the treatment of metastatic ER+/HER2- breast cancer (mBC) in combination with endocrine therapy. Although this class of inhibitor has been extensively studied in several other cancer types, CDK4/6 inhibitors have not been approved as a treatment for outside of ER+/HER2- cancer. We evaluated the clinically approved CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib—in a 500+ cell line screening platform and identified several cancers outside of breast that may have subpopulations that are sensitive to CDK4/6 inhibitors. Kinome and KiNativ analyses helped identify differences in sensitivity/selectivity that we observed between each CDK4/6 inhibitor. Comprehensive molecular profiling of the cell lines at baseline allowed us to screen for potential associations with sensitivity to these compounds. These analyses identified potential biomarkers of sensitivity in non-small cell lung carcinoma (NSCLC) and colorectal cancer (CRC) that will later be evaluated in human clinical studies. Having thoroughly studied the CDK4/6 class and discovered new opportunities for clinical development, we set out to develop a CDK4/6 inhibitor that would have the best properties of the two distinguished class members. Using our proprietary chemistry, we developed UCT-03-008, a potent CDK4/6 small molecular inhibitor with a pharmacology known to enhance therapeutic benefit in mBC. Pharmacokinetic properties of UCT-03-008 are improved over those of other CDK4/6 inhibitors. UCT-03-008 has activity in preclinical models as a monotherapy and yields in vivo efficacy in multiple cancer models outside of ER+/HER2- breast cancer, including CRC and NSCLC. In summary, UCT-03-008 is a CDK4/6 inhibitor with optimized pharmacological properties. Clinical development of this compound will be guided by the biomarker hypotheses developed here. We are currently enrolling patients for treatment with UCT-03-008 in a Phase 1 clinical trial of advanced solid tumors (NCT05103046). Citation Format: Neil A. O'Brien, Martina S. McDermott, Brendan M. O'Boyle, Justin A. Hilf, Oliver Loson, Kevin Chau, Weiping Jia, Naeimeh Kamranpour, Tong Luo, Raul Ayala, Shawnt Issakhanian, John A. Glaspy, Brian M. Stoltz, Dennis J. Slamon. Development and characterization of a novel CDK4/6 inhibitor for the treatment of CDK4/6 dependent cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5991.