TY - JOUR
T1 - Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain
AU - Shukla, Shirish
AU - Ying, Weijiang
AU - Gray, Felicia
AU - Yao, Yiwu
AU - Simes, Miranda L.
AU - Zhao, Qingjie
AU - Miao, Hongzhi
AU - Cho, Hyo Je
AU - González-Alonso, Paula
AU - Winkler, Alyssa
AU - Lund, George
AU - Purohit, Trupta
AU - Kim, EunGi
AU - Zhang, Xiaotian
AU - Ray, Joshua M.
AU - He, Shihan
AU - Nikolaidis, Caroline
AU - Ndoj, Juliano
AU - Wang, Jingya
AU - Jaremko, Lukasz
AU - Jaremko, Mariusz
AU - Ryan, Russell J. H.
AU - Guzman, Monica L.
AU - Grembecka, Jolanta
AU - Cierpicki, Tomasz
N1 - KAUST Repository Item: Exported on 2021-06-23
Acknowledgements: 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.
PY - 2021/6/21
Y1 - 2021/6/21
N2 - 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.
AB - 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.
UR - http://hdl.handle.net/10754/669743
UR - http://www.nature.com/articles/s41589-021-00815-5
U2 - 10.1038/s41589-021-00815-5
DO - 10.1038/s41589-021-00815-5
M3 - Article
C2 - 34155404
SN - 1552-4450
JO - Nature Chemical Biology
JF - Nature Chemical Biology
ER -
