Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain

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.

Shukla, S., Ying, W., Gray, F., Yao, Y., Simes, M. L., Zhao, Q., … Cierpicki, T. (2021). Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain. Nature Chemical Biology. doi:10.1038/s41589-021-00815-5

This work was funded by the National Institute of Health (NIH) R01 grants CA207272, CA226759 and CA240514 to T.C., CA201204, CA244254 and CA160467 to J.G. and LLS Scholar grants (1340-17) to T.C. and (1215-14) to J.G. This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract number DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (grant 085P1000817). TEX and MLL–ENL cells were received from J. Dick, University Health Network, Toronto, Canada. We thank M. Carroll and G. Danet-Desnoyers from the Stem Cell and Xenograft Core at the University of Pennsylvania for providing a human AML primary sample.

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