Discovery 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 1 (MS181). We show that 1 induces preferential degradation of PRC1 components, BMI1 and RING1B,
in an EED-, CRBN-, and ubiquitin-proteosome system (UPS)-dependent
manner. Compound 1 also has superior antiproliferative
activity in multiple metastatic cancer cell lines over EED-binding
PRC2 degraders and can be efficacious in VHL-defective cancer cells.
Altogether, compound 1 is a valuable chemical biology
tool to study the role of PRC1 in cancer. Importantly, we show that
CRBN can be utilized to develop bridged PROTACs, expanding the bridged
PROTAC technology for degrading undruggable proteins.