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

作者：William M. 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, Débora Bonenfant, Markus Warmuth, Filip Janku, Magnus W. Walter, Sharon A. Townson, Bernhard Fasching, Simone Totoioli, Christopher King, L. L. McAllister, B. Ranieri, Sofia Gkountela, Ralph Tiedt, Nina Ilic Widlund · 发表于：Cancer Research · 年份：2026 · DOI：10.1158/1538-7445.am2026-6778 · 研究领域：Protein Degradation and Inhibitors、Cancer-related Molecular Pathways、Advanced Breast Cancer Therapies

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...