Abstract 7002: Discovery of DXTX-1464: A first-in-class, highly potent and selective degrader of CCNE1/CCNE2 and CDK2 for cancer therapy

Abstract Introduction: Cyclin E1 (CCNE1) and E2 (CCNE2) when amplified are a hallmark of several aggressive cancers, including ovarian, gastric, and endometrial. These cyclins, when overexpressed, bind and activate CDK2, driving uncontrolled cell cycle progression and contributing to treatment resistance, particularly to CDK4/6 inhibitors in breast cancer. The persistent activation of CCNE1/CCNE2-CDK2 complexes is also linked to poor clinical outcomes in many solid tumors. In addition, kinase-independent functions of Cyclin E have been demonstrated to regulate cell cycle and affect genome stability. Selectively targeting the degradation of CCNE1, CCNE2, and CDK2 offers a promising strategy to dismantle this oncogenic axis, overcome therapeutic resistance, and improve patient outcomes. Results: Prospective design informed by Auto/dx, a proprietary platform for predicting degrader pharmacology, elucidated multiple series of dual Cyclin E and CDK2 degraders designed to enable preferential stabilization of a ternary complex conformation enabling lysine-specific targeting of a ubiquitination zone between CDK2 and CCNE1/CCNE2, selectively targeting these proteins for degradation via the ubiquitin-proteasome system. These bivalent degraders incorporate a ligand that binds CDK2 and a cereblon-binding moiety, connected by an optimized linker that induces cooperativity and novel protein-protein interaction surfaces between CDK2 and cereblon. Functional studies demonstrated that these degraders effectively eliminated CCNE1, CCNE2, and CDK2 while sparing other cyclins and CDKs. Selective degradation of CCNE1/CCNE2-CDK2 complexes by development candidate DXTX-1464 resulted in potent inhibition of downstream signaling, including phosphorylation of Rb, a critical mediator of cell cycle progression and resulted in the upregulation of p21 and p27. This led to cell cycle arrest, the induction of apoptosis in some contexts, and significant antiproliferative effects in cancer models with CCNE1/CCNE2 dependencies. In vivo studies further validated these results, achieving robust depletion of CCNE1, CCNE2, and CDK2 in tumor models, leading to measurable tumor regression. 14 day DRF studies have indicated DXTX-1464 is well tolerated in rat and dog at doses exceeding the DC90. Conclusions: Targeted degradation of CCNE1, CCNE2, and CDK2 represents a novel therapeutic approach for cancers characterized by Cyclin E dependencies or CDK2 hyperactivation. By eliminating CCNE1/CCNE2-CDK2 complexes, we propose this strategy will circumvent resistance to CDK4/6 inhibitors in HR+/HER2− breast cancers and will address oncogenic signaling in Cyclin E-amplified or overexpressed solid tumors. These findings support the further development of CCNE1/CCNE2 degraders and provide a rationale for their clinical application in patients with Cyclin E-driven malignancies. Citation Format: Tim Dwight, Andrew Allen, Vivian Guo, Justin Radatti, Stephane Corbel, Stephane Billotte, Paul Greenspan, MIke Wood, Humphrey Gardner, Bryce Kenneth Allen. Discovery of DXTX-1464: A first-in-class, highly potent and selective degrader of CCNE1/CCNE2 and CDK2 for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7002.