Abstract 2568: ARTS-021 is a potent and selective CDK2 inhibitor that demonstrates anti-cancer activity in preclinical cancer models with CCNE1 amplification

Abstract Cyclin E1 amplification is prevalent in cancers with high unmet medical need such as high grade serous ovarian cancer, stomach cancer and esophageal cancer. Cancer cell lines with high expression level of cyclin E1 gene exhibited profound sensitivity to CDK2 gene depletion, suggesting CDK2 selective inhibitors have the potential to treat patients harboring Cyclin E1 alterations. Here we report the development and preclinical characterization of ARTS-021, an orally bioavailable small molecule CDK2 selective inhibitor. In enzymatic assay against a panel of different CDKs, ARTS-021 potently inhibits the activity of CDK2/CyclinE1 complex with 50% inhibitory concentration (IC50) in the sub-nanomolar range, displaying superior selectivity against other CDKs (CDK1,4,6,7,9). Very low hit rate (S(10)=0.022, at 1uM) is observed when ARTS-021 is assessed in whole Kinome profiling, further revealing the selectivity of this compound. ARTS-021 also demonstrates potent CDK2 inhibition and selectivity against other CDK family members (CDK1,4,6,9) in a series of cellular assays. Consistent with genetic CDK2 dependence data, cell lines with CCNE1 amplification are particularly sensitive to ARTS-021. Double nanomolar ARTS-021 inhibits Rb phosphorylation and blocks G1/S transition, leading to cell growth arrest specifically in CCNE1 amplified cell lines. This CDK2 dependent anti-tumor activity is further validated in vivo, where daily ARTS-021 administration leads to tumor stasis in CCNE1 amplified but not wild type xenograft models. Taken together, these data demonstrate ARTS-021 as a promising CDK2 selective inhibitor with strong potential towards the development of effective therapies for CCNE1 altered cancer. Citation Format: jiaqi Liang, Dai Cheng, Yali Guo, xiaobin zhang, Xipan Liu, Jia Fu, Qiang Ding, Wen Xiong, Fang Li, Yaoyu Chen, Qing Sheng. ARTS-021 is a potent and selective CDK2 inhibitor that demonstrates anti-cancer activity in preclinical cancer models with CCNE1 amplification [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 2568.