Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain

• Published in: Nature chemical biology Vol. 17; no. 7; pp. 784 - 793
• Main Authors: Shukla, Shirish, Ying, Weijiang, Gray, Felicia, Yao, Yiwu, Simes, Miranda L., Zhao, Qingjie, Miao, Hongzhi, Cho, Hyo Je, González-Alonso, Paula, Winkler, Alyssa, Lund, George, Purohit, Trupta, Kim, EunGi, Zhang, Xiaotian, Ray, Joshua M., He, Shihan, Nikolaidis, Caroline, Ndoj, Juliano, Wang, Jingya, Jaremko, Łukasz, Jaremko, Mariusz, Ryan, Russell J. H., Guzman, Monica L., Grembecka, Jolanta, Cierpicki, Tomasz
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2021; Nature Publishing Group
• Subjects: 631/154/309/2420; 631/535/878; 631/92; 631/92/613; 631/92/96; Acute myeloid leukemia; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Blocking; Cell Biology; Cell differentiation; Cell Differentiation - drug effects; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Chromatin; Domains; Dose-Response Relationship, Drug; Histone H2A; Humans; Hydrophobicity; Inhibitors; K562 Cells; Leukemia; Models, Molecular; Molecular Structure; Myeloid leukemia; Optimization; Polycomb group proteins; Polycomb Repressive Complex 1 - antagonists & inhibitors; Polycomb Repressive Complex 1 - genetics; Polycomb Repressive Complex 1 - metabolism; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Tumor cell lines; Ubiquitin-protein ligase; Ubiquitination; Ubiquitination - drug effects
• ISSN: 1552-4450; 1552-4469; 1552-4469
• DOI: 10.1038/s41589-021-00815-5

Polycomb repressive complex 1 (PRC1) is an essential chromatin-modifying complex that monoubiquitinates histone H2A and is involved in maintaining the repressed chromatin state. Emerging evidence suggests PRC1 activity in various cancers, rationalizing the need for small-molecule inhibitors with well-defined mechanisms of action. Here, we describe the development of compounds that directly bind to RING1B–BMI1, the heterodimeric complex constituting the E3 ligase activity of PRC1. These compounds block the association of RING1B–BMI1 with chromatin and inhibit H2A ubiquitination. Structural studies demonstrate that these inhibitors bind to RING1B by inducing the formation of a hydrophobic pocket in the RING domain. Our PRC1 inhibitor, RB-3, decreases the global level of H2A ubiquitination and induces differentiation in leukemia cell lines and primary acute myeloid leukemia (AML) samples. In summary, we demonstrate that targeting the PRC1 RING domain with small molecules is feasible, and RB-3 represents a valuable chemical tool to study PRC1 biology. Fragment screening and medicinal chemistry optimization led to development of a small-molecule inhibitor of RING1B–BMI1 E3 ligase, blocking the H2A ubiquitination activity of the Polycomb repressive complex 1 and inducing differentiation in leukemia cells.