Abstract 5642: Discovery of SCR-8079, a novel and selective CDK2/4/6 inhibitor overcomes the resistance to CDK4/6 inhibition and demonstrates broad anti-tumor activities in breast cancers

Abstract

Abstract The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival and overall survival in HR positive and HER2-negative breast cancer in combination either with letrozole or fulvestrant. However, resistance to the CDK4/6 inhibition inevitably develops. Preclinical models and clinical transcriptome specimen analysis disclosed that abnormal activation of Cyclin E/CDK2 due to CCNE gene amplification was one of the major reasons to CDK4/6 inhibition resistance. And inhibition of CDK2 either by gene knockdown of CCNE or by pharmaceutic approach rescued the sensitivity of resistant tumor cells to CDK4/6 inhibition. To overcome the resistance, a novel and selective CDK2/4/6 inhibitor, SCR-8079 was developed. In biochemical assay, SCR-8079 was demonstrated high potency on inhibiting CDK2/4/6 with IC50 of 3 nM, 1 nM and 2 nM, respectively. And SCR-8079 showed good selectivity over CDK1/9 isoforms (>60 selectivity folds). SCR-8079 demonstrated closed inhibitory activities both on CDK4/6 sensitive and resistant lines. In MCF-7, a breast cancer cell line sensitive to PAL, SCR-8079 potently inhibited Rb phosphorylation (IC50, 53 nM) and cell proliferation (IC50, 28 nM). Meanwhile, SCR-8079 showed high potency on inhibiting on the growth of OVCAR3, an ovarian cancer cell line with elevated CDK2 activation and resistance to PAL. SCR-8079 inhibited Rb phosphorylation (IC50, 41 nM) and cell proliferation (IC50, 21 nM). In order to further mimic CDK4/6 resistance, a PAL resistant line (MCF-7R) was generated via induction of MCF-7 by gradient increased PAL. SCR-8079 potently inhibited MCF-7R cells growth (IC50, 3 nM) but PAL didn’t (IC50 >1 µM). Moreover, SCR-8079 showed high potency on growth inhibition in a broad of breast cancer cell lines, including HR-positive, Her2-positive and triple negative lines. SCR-8079 displayed good oral bioavailability in multiple pre-clinical species and robust anti-tumor activities both in OVCAR3 and MCF7 xenograft models. In summary, SCR-8079 is a selective CDK2/4/6 inhibitor, which overcomes the CCNE-mediated resistance to CDK4/6 inhibition. Broad anti-tumor activity suggests SCR-8079 central role in breast cancer treatment. Citation Format: Feng Zhou, Guimei Yang, Feng Tang, Yan Zhang, Wenqing Yang, Liting Xue, Ping Chen, Renhong Tang. Discovery of SCR-8079, a novel and selective CDK2/4/6 inhibitor overcomes the resistance to CDK4/6 inhibition and demonstrates broad anti-tumor activities in breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5642.