Abstract 6778: Selective targeting of CCNE1 using molecular glue degraders for the treatment of <i>CCNE1</i> amplified cancers

Abstract Cyclin E1 (CCNE1) is a critical driver of cell cycle progression and cell proliferation. It acts as the regulatory subunit for the CCNE1-CDK2 holoenzyme, which coordinates cell cycle progression through the G1/S phases and effectively drives cell proliferation via RB phosphorylation and repression. CCNE1 is frequently amplified or overexpressed across multiple cancer types, including ovarian, endometrial, gastric, breast, and others, and thus pharmacological targeting of CCNE1 is expected to benefit patients whose cancers bear these alterations. Despite the clear therapeutic promise of directly targeting CCNE1 in these patients, CCNE1 has been considered undruggable by conventional means as it is a regulatory non-enzymatic protein. Hence, we sought to identify molecular glue degraders (MGDs) that selectively target CCNE1 for proteasomal degradation. Using our MGD discovery engine QuEENTM encompassing biochemical and cellular assays as well as in silico modelling, we identified and optimized molecules that potently degrade CCNE1. Leveraging a cryptic pocket, our CCNE1 MGDs selectively degrade the cyclin E1/CDK2 holoenzyme complex, while sparing other proteins such as closely related cyclins or CDKs. In CCNE1 amplified cancer cell lines CCNE1 MGDs selectively inhibit cellular proliferation, while sparing cell lines without amplification, in line with the “oncogenic addiction” paradigm. These anti-proliferative effects were determined to be governed by downmodulation of RB phosphorylation and E2F-driven gene expression, attesting to the on-target function of our CCNE1 MGDs. When assessed in vivo, orally dosed CCNE1 MGDs induced robust tumor growth suppression and regression as a monotherapy in CCNE1 amplified ovarian, breast, and gastric models. We further established that clinical stage CDK2 inhibitors exhibit significant off-target activity through kinome profiling and genetic modeling, demonstrating the superior selectivity of CCNE1 MGDs. Owing to their exquisite selectivity, we expect that CCNE1 MGDs will avoid dose-limiting toxicities associated with less selective CDK2 inhibitors. CCNE1 MGDs represent a first in class opportunity and a paradigm shift due to their ability to directly target a frequently amplified non-enzymatic driver oncogene in distinct populations of cancer patients with high unmet medical need. With their distinctive ability to spare other proteins whose inhibition is associated with dose-limiting toxicities, CCNE1 MGDs offer a unique precision medicine angle for populations in desperate need of treatment options. 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 Totoioli, Christopher King, Laura McAllister, Beatrice Ranieri, Sofia Gkountela, Ralph Tiedt, Nina Ilic Widlund. Selective targeting of CCNE1 using molecular glue degraders for the treatment of CCNE1 amplified cancers [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 6778.