发现一种选择性靶向CCNE1的分子胶降解剂，用于治疗CCNE1扩增的实体瘤和CDK4/6i耐药的HR+/HER2-乳腺癌

Cyclin E1 (CCNE1) is a central regulator of the G1 to S-phase transition of the cell cycle and a key dependency in multiple solid tumor types, including ovarian and endometrial cancers, and promotes resistance to CDK4/6 inhibitors in HR+/HER2- breast cancer. CCNE1 lacks a druggable pocket or enzymatic activity, which has precluded attempts to develop drugs that inhibit its function. Efforts to inhibit CCNE1 activity indirectly with CDK2 kinase inhibitors have been hindered by poor selectivity and dose-limiting toxicities that prevent full pathway suppression. Here we report the discovery of a molecular glue degrader (MGD) that co-opts the CRL4 CRBN E3 ubiquitin ligase to eliminate the CCNE1 protein. Single-particle cryo-electron microscopy identifies a novel non-G-loop degron on CCNE1 that drives direct recognition of CCNE1 by the MGD:CRBN:DDB1 complex without preventing CDK2 binding to CCNE1. In cell lines analyzed, MGD treatment triggers rapid, CRBN-dependent depletion of CCNE1 with complete selectivity over the rest of the proteome. MGD-induced CCNE1 degradation exerts potent and selective anti-proliferative effects, with over 500-fold greater potency in CCNE1 amplified lines compared to non-amplified lines, a substantial improvement relative to CDK2 inhibitors (~15-fold potency window). In HR+/HER2- breast cancer cell lines with evolved resistance to the combination of a CDK4/6 inhibitor and fulvestrant, co-treatment with the MGD restores sensitivity. Oral administration of the MGD drives robust CCNE1 reduction and antitumor activity in a CCNE1-amplified xenograft model. These data suggest that directly and selectively degrading CCNE1 could provide an effective targeted therapy for CCNE1-amplified solid tumors and overcome resistance to CDK4/6 inhibitors in HR+/HER2- breast cancer.