Abstract PR003: Targeting the “undruggable” oncogene CCNE1 using a molecular glue degrader in CCNE1 amplified cancers

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Abstract Using our QuEENTM molecular glue degrader (MGD) discovery engine that integrates biochemical and cellular assays with in silico modeling, we identified and optimized MGDs that induce proteasomal degradation of cyclin E1 (CCNE1) as a therapeutic strategy for CCNE1-amplified cancers. We generated a highly selective CCNE1 degrader that spares related cyclins and other proteins. CCNE1 is a key regulator of G1/S cell-cycle progression. As the regulatory subunit of the CCNE1–CDK2 holoenzyme, it promotes RB phosphorylation, relieves RB-mediated repression, and drives proliferation. CCNE1 is frequently amplified and/or overexpressed across multiple tumor types (including ovarian, endometrial, gastric, and breast cancers), making it an attractive therapeutic target. However, as a non-enzymatic regulatory protein, CCNE1 has been considered difficult to drug with conventional approaches. Our CCNE1 MGD selectively inhibited proliferation of CCNE1-amplified cancer cell lines while sparing non-amplified lines, consistent with the hypothesis that CCNE1 amplification is an indication of oncogene addiction. The antiproliferative phenotype was accompanied by markedly reduced RB phosphorylation and suppression of E2F-driven transcription, supporting an on-target mechanism of action. In addition, we observed strong induction of senescence markers in CCNE1 MGD-treated cells, indicating an exit from the cell cycle. In in vivo studies, orally dosed CCNE1 MGD produced robust tumor growth inhibition and regression as monotherapy in CCNE1-amplified ovarian, breast, and gastric models. Multiple CDK2 kinase inhibitors are in clinical development for CCNE1-amplified cancers. Through kinome profiling and genetic modeling, we found that clinical-stage CDK2 inhibitors can exhibit substantial off-target activity, highlighting the differentiated selectivity profile of the CCNE1 MGD and supporting the potential for improved tolerability versus less selective CDK2 inhibition. To model potential CCNE1 MGD and CDK2 inhibitor toxicity in vitro, we conducted colony-forming unit (CFU) assays with normal human erythroid and myeloid progenitor cells. While CDK2 inhibitors reduced both erythroid and myeloid colony formation, our CCNE1 MGD had no effect on either lineage, further supporting their potential for superior tolerability. These observations are in line with the recently completed dose-range finding toxicology studies for our CCNE1 MGD in rats and cynomolgus monkeys, where no adverse events were noted, as shown by in-life observations, histopathology, and clinical chemistry. In conclusion, CCNE1 MGD provides a first-in-class approach to directly target a frequently amplified, non-enzymatic driver oncogene and represents a differentiated precision medicine strategy for patients with CCNE1-altered cancers. Citation Format: William Tahaney, Yimao Liu, Ahmed Abdullah, Vittoria Massafra, Verena Lang, Markus Baumann, Aurelie Dubois, Arnaud Osmont, Xavier Lucas, Chao Quan, Anna Kostikova, Anna Diesslin, Freya Harvey, Christelle Bianda, Kevin Larpenteur, Katherine Jones, Anne-Cecile D’Alessandro, Carolina Perdomo Ortiz, Herve Farine, Maciej Cabanski, Manav Korpal, Bradley Demarco, Debora Bonenfant, Markus Warmuth, Filip Janku, Magnus Walter, Sharon Townson, Bernhard Fasching, Simone Tortoioli, Chris King, Laura McAllister, Sofia Gkountela, Beatrice Ranieri, Ralph Tiedt, Nina Ilic-Widlund. Targeting the “undruggable” oncogene CCNE1 using a molecular glue degrader in CCNE1 amplified cancers [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr PR003.

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