Abstract P5-01-26: Selective Targeting of CDK2 Using Molecular Glue Degraders for the Treatment of HR-Positive/HER2-Negative Breast Cancer

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Abstract Cyclin dependent kinases 4 and 6 (CDK4 and CDK6) and cyclin dependent kinase 2 (CDK2) act sequentially to coordinate cell cycle progression through the G1/S phases and effectively drive cell proliferation via RB phosphorylation and repression. CDK4/6 inhibitors in combination with endocrine therapy are approved agents for the treatment of hormone-receptor (HR)-positive/HER2-negative breast cancer. While these agents offer substantial benefit, patients eventually relapse. It has been reported that approximately 30% of resistant tumors following CDK4/6 inhibitor treatment exhibit upregulation of CCNE1 expression, and others are thought to adapt to chronic CDK4/6-inhibition by increased tumor reliance on the CDK2 pathway to sustain downstream signaling along the RB-E2F axis. Hence, targeting CDK2 in conjunction with CDK4/6 inhibition is expected to provide more sustained responses in this difficult-to-treat patient population. We sought to identify molecular glue degraders (MGDs) that selectively target CDK2. Using our MGD discovery engine QuEENTM encompassing biochemical and cellular assays as well as in silico modelling, we identified and further optimized molecules that induce CRBN engagement and selective degradation of CDK2, while sparing other proteins such as closely related CDKs. Unlike CDK2 inhibitors, CDK2 MGD inhibits cell proliferation in an RB-dependent manner, attesting to its superior selectivity. Furthermore, this MGD induces robust downstream pathway suppression, as evidenced by downmodulation of RB phosphorylation and E2F-driven gene expression. When dosed orally in preclinical models of HR-positive/HER2-negative breast cancer, this compound drives deep tumor regression in combination with CDK4/6 inhibitor or triple combination with endocrine therapy (fulvestrant), resulting in enhanced downstream pathway suppression compared to CDK4/6 inhibitor alone. Owing to its superior selectivity, we expect that a CDK2 MGD will avoid dose-limiting toxicities associated with less selective CDK2 inhibitors. Hence, a CDK2 MGD provides novel means to target an inadequately drugged target, offering a unique angle for populations in desperate need of treatment options. Citation Format: Nina Ilic-Widlund, William Tahaney, Vasia Vafeiadou, Christelle Bianda, Liam Cheeseman, Ambika Singh, Anna Diesslin, Sophia Nguyen, Luca Moccia, Christopher King, Yimao Liu, Chao Quan, Xavi Lucas, Vladas Oleinikovas, Bradley Demarco, Laura Schwander, Vaik Strande, Jessica Alers, Rajiv Narayan, Dave Peck, Sarah Pessa, Samuel Gilberto, John Castle, Sharon Townson, Markus Warmuth, Magnus Walter, Ralph Tiedt, Andreas Ritzen, Beatrice Ranieri, Sofia Gkountela. Selective Targeting of CDK2 Using Molecular Glue Degraders for the Treatment of HR-Positive/HER2-Negative Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-01-26.

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