biostudies-literatureKabir MNational Institutes of HealthNIH HHSIcahn School of Medicine at Mount Sinai6880-6892https://www.ebi.ac.uk/biostudies/studies/S-EPMC11069391biostudies-literatureUnknown67(8)Bridged PROTAC is a novel protein complex degrader strategy that exploits the target protein's binding partner to degrade undruggable proteins by inducing proximity to an E3 ubiquitin ligase. In this study, we discovered for the first time that cereblon (CRBN) can be employed for the bridged PROTAC approach and report the first-in-class CRBN-recruiting and EED-binding polycomb repressive complex 1 (PRC1) degrader, compound <b>1</b> (MS181). We show that <b>1</b> induces preferential degradation of PRC1 components, BMI1 and RING1B, in an EED-, CRBN-, and ubiquitin-proteosome system (UPS)-dependent manner. Compound <b>1</b> also has superior antiproliferative activity in multiple metastatic cancer cell lines over EED-binding PRC2 degraders and can be efficacious in VHL-defective cancer cellsJournal of medicinal chemistryDiscovery and Characterization of a Novel Cereblon-Recruiting PRC1 Bridged PROTAC Degrader.PMC110693911S10OD025132S10 OD0251321S10OD028504S10 OD028504Xiong YQin LLuo KSidi RAKabir MJin JPark KSfalseDiscovery and Characterization of a Novel Cereblon-Recruiting PRC1 Bridged PROTAC Degrader.Bridged PROTAC is a novel protein complex degrader strategy that exploits the target protein's binding partner to degrade undruggable proteins by inducing proximity to an E3 ubiquitin ligase. In this study, we discovered for the first time that cereblon (CRBN) can be employed for the bridged PROTAC approach and report the first-in-class CRBN-recruiting and EED-binding polycomb repressive complex 1 (PRC1) degrader, compound <b>1</b> (MS181). We show that <b>1</b> induces preferential degradation of PRC1 components, BMI1 and RING1B, in an EED-, CRBN-, and ubiquitin-proteosome system (UPS)-dependent manner. Compound <b>1</b> also has superior antiproliferative activity in multiple metastatic cancer cell lines over EED-binding PRC2 degraders and can be efficacious in VHL-defective cancer cells2024-01-01T00:00:00Z2024 Apr2026-06-02T06:37:30.221Z2026-04-15T03:15:18.45ZS-EPMC110693913860731810.1021/acs.jmedchem.4c00538