Abstract 5780: Discovery of ATH-007, a novel, potent and highly selective CCNE1 molecule glue shows robust anti-tumor activities and better safety profile

Abstract Cyclin E1 (CCNE1) is a key cell cycle regulatory protein and binds to cyclin-dependent kinase 2 (CDK2), forming a CCNE1-CDK2 complex, which is essential for driving the cell cycle progression to S-phase for subsequent DNA replication. Amplification of the CCNE1 locus on chromosome 19q12 is prevalent in multiple tumor types, particularly in breast cancer, high-grade serous ovarian cancer, uterine tumors, and gastro-esophageal cancers. In breast cancer, amplification of CCNE1 is a potential cause of resistance to CDK4/6 inhibitor. CCNE1 amplification may also confer resistance to chemotherapy and is associated with poor overall survival. Therefore, there is a significant unmet medical need for tumors with CCNE1 amplification. Compared with CDK2 inhibitors, CCNE1 molecular glues exhibit better selectivity, thereby reducing the adverse effects caused by CDK2 inhibitors in clinical trials. Here, we report that ATH-007 is a highly selective CCNE1 degrader that demonstrates superior degradation selectivity and anti-tumor activity against CCNE1-amplified cells. ATH-007 strongly degrades CCNE1 with DC50 of <10 nM and achieves complete protein degradation (Dmax of >95%) and also shows 1000-fold degradation selectivity over other CRBN substrates, including GSPT1, CK1α, and IKZF1, etc. ATH-007 can effectively inhibit the proliferation of MKN1 cells with CCNE1 amplification, however, after the deletion of RB1 (a downstream substrate of CCNE1), the inhibitory effect of ATH-007 on MKN1-RB1-KO cells is abrogated. Across a panel of CCNE1-amplified tumor cell lines, ATH-007 potently inhibits proliferation with GI50 values ranging from 1 to 100 nM, similar to the potency of CDK2 inhibitors. In CCNE1-non-amplified cells, ATH-007 exhibits significantly superior selectivity compared to CDK2 inhibitors, rendering it the greater therapeutic window. In terms of in vitro hematotoxicity assay, ATH-007 shows no inhibitory effect on the differentiation of all lineages, while CDK2 inhibitors exhibits a strong inhibitory effect. Compared with existing CCNE1 molecular glues, ATH-007 exhibits weaker inhibition of hERG, indicating that it has potentially better safety. ATH-007 exhibits favorable PK properties, which enable us to advance this molecule to in vivo experiments. In tumor model with CCNE1 amplification, ATH-007 shows tumor suppression activity even at low doses and inhibit tumor growth in a dose-dependent manner. Furthermore, the inhibitory activity against tumors is correlated with the degradation of CCNE1. Citation Format: Zhiyong Yu, Wenming Li, Yuyao Zhang, Wenwen Zhao, Youxi Chen, Feng Zhou, . Discovery of ATH-007, a novel, potent and highly selective CCNE1 molecule glue shows robust anti-tumor activities and better safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5780.