Targeted degradation of PRC1 components, BMI1 and RING1B, via a novel protein complex degrader strategy

Abstract

AbstractPolycomb repressive complex 1 (PRC1) is an essential epigenetic regulator that mainly controls histone H2A Lys119 mono-ubiquitination (H2AK119ub). BMI1 and RING1B are PRC1 core components and play critical roles in the development of various cancers. However, therapeutic agents targeting PRC1 are very limited, and small-molecule inhibitors of PRC1 displayed limited effectiveness in killing cancer cells. In this study, MS147, the first degrader of PRC1 core components, BMI1 and RING1B, was discovered via a novel protein complex degradation strategy that utilizes the target protein’s interacting partner protein (EED) to degrade BMI1 and RING1B. MS147, which comprises an EED small-molecule binder linked to a ligand of the E3 ligase VHL, degrades BMI1 and RING1B in an EED-, VHL-, ubiquitination- and time-dependent manner. MS147 is selective and preferentially degrades BMI1 and RING1B over PRC2 core components: EED, EZH2 and SUZ12. Consequently, MS147 effectively reduces H2AK119ub, but not H3K27me3, which is catalyzed by PRC2. Furthermore, MS147, but not the parent EED binder or known PRC2 degraders, effectively inhibits the proliferation of cancer cell lines that are insensitive to EZH2 knockout or PRC2 degraders. Overall, this study provides a novel degrader targeting BMI1 and RING1B, which is a useful chemical tool to further investigate the roles of PRC1 in cancer, and a novel protein complex degradation strategy, which could potentially expand the degradable human proteome.