Targeted Degradation of PRC1 Components, BMI1 and RING1B, via a Novel Protein Complex Degrader Strategy. Issue 10 (3rd February 2023)

• Record Type: Journal Article
• Authors: Park, Kwang‐Su; Qin, Lihuai; Kabir, Md; Luo, Kaixiu; Dale, Brandon; Zhong, Yue; Kim, Arum; Wang, Gang Greg; Kaniskan, Husnu Ümit; Jin, Jian
• Is Part Of: Advanced science. Volume 10:Issue 10(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-02-03
• Subjects: BMI1 -- degrader -- embryonic ectoderm development (EED) -- polycomb repressive complex 1 (PRC1) -- proteolysis targeting chimera (PROTAC) -- RING1B; Science -- Periodicals; 505
• DOI: 10.1002/advs.202205573
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: Polycomb repressive complex 1 (PRC1) is an essential epigenetic regulator that mainly controls histone H2A Lys119 mono‐ubiquitination (H2AK119ub). B cell‐specific Moloney murine leukemia virus Integration site 1 (BMI1) and really interesting new gene 1B (RING1B) are PRC1 core components and play critical roles in the development of various cancers. However, therapeutic agents targeting PRC1 are very limited. In this study, MS147, the first degrader of PRC1 core components, BMI1 and RING1B, is discovered via a novel protein complex degradation strategy that utilizes the target protein's interacting partner protein (embryonic ectoderm development (EED)). MS147, which comprises an EED small‐molecule binder linked to a ligand of the E3 ligase von Hippel‐Lindau (VHL), degrades BMI1/RING1B in an EED‐, VHL‐, ubiquitination‐, and time‐dependent manner. MS147 preferentially degrades BMI1/RING1B over polycomb repressive complex 2 (PRC2) core components. Consequently, MS147 effectively reduces H2AK119ub, but not histone H3 Lys27 tri‐methylation (H3K27me3), which is catalyzed by PRC2. Furthermore, MS147 effectively inhibits the proliferation of cancer cell lines that are insensitive to PRC2 inhibitors/degraders. Overall, this study provides a novel BMI1/RING1B degrader, which is a useful chemical tool to further investigate the roles of PRC1 in cancer, and a novel protein complex degradation strategy, which can potentially expand the degradable human proteome. Abstract : The first degrader of BMI1 and RING1B is achieved via a novel protein complex degrader strategy, which utilizes an EED small‐molecule binder linked to a ligand of the E3 ligase von Hippel‐Lindau to preferentially degrade PRC1 components, BMI1 and RING1B, over EED, by hijacking the ubiquitin‐proteasome system.