Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain

Shukla, Shirish; Ying, Weijiang; Gray, Felicia; Yao, Yiwu; Simes, Miranda L; Zhao, Qingjie; Miao, Hongzhi; Cho, Hyo Je; Gónzález-Alonso, Paula; Winkler, Alyssa; Lund, George; Purohit, Trupta; Kim, Eungi; Zhang, Xiaotian; Ray, Joshua M; He, Shujiao; Nikolaidis, Caroline; Ndoj, Juliano; Wang, Jingya; Jaremko, Łukasz; Jaremko, Mariusz; Ryan, Russell J.; Guzmán, Mónica L.; Grembecka, Jolanta; Cierpicki, Tomasz

doi:10.1038/s41589-021-00815-5

Cited by 49 publications

(28 citation statements)

References 60 publications

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“…To circumvent these disadvantages, specific inhibitors targeting subunits of PcG complexes can be leveraged. As many PcG genes, like EZH2 or PCGF4, are considered oncogenes, research efforts have been invested in the development of efficient and highly specific inhibitors (an extensive list of inhibitors can be found in , many of which have already been utilized for functional analysis of PcG regulation (Hojfeldt et al, 2018;Miller et al, 2021;Shukla et al, 2021;van Mierlo et al, 2019;Wang, Alpsoy, et al, 2021) 2021) introduced a small-molecule inhibitor that binds to the RING domains of RING1B and RING1A, thereby inhibiting E3 ligase activity of the canonical PRC1 complexes through disruption of the PRC1 interaction with chromatin. PcG inhibitors are not only potent therapeutics, but also valuable tools for future studies of PcG activity and function.…”

Section: Specific Inhibitors Of Pcg Protein Functionmentioning

confidence: 99%

“…To circumvent these disadvantages, specific inhibitors targeting subunits of PcG complexes can be leveraged. As many PcG genes, like EZH2 or PCGF4, are considered oncogenes, research efforts have been invested in the development of efficient and highly specific inhibitors (an extensive list of inhibitors can be found in Wang, Ordonez‐Rubiano, et al., 2021), many of which have already been utilized for functional analysis of PcG regulation (Hojfeldt et al., 2018; Miller et al., 2021; Shukla et al., 2021; van Mierlo et al., 2019; Wang, Alpsoy, et al., 2021). Inhibitor treatment of ESCs could recapitulate findings made in Ezh2 knockout cells, with both H3K27me3 as well as DNA methylation being affected by the depletion of PRC2 (van Mierlo et al., 2019).…”

Section: Experimental Approaches To Study Pcg Regulation In Human Cor...mentioning

confidence: 99%

“…Shukla et al. (2021) introduced a small‐molecule inhibitor that binds to the RING domains of RING1B and RING1A, thereby inhibiting E3 ligase activity of the canonical PRC1 complexes through disruption of the PRC1 interaction with chromatin. PcG inhibitors are not only potent therapeutics, but also valuable tools for future studies of PcG activity and function.…”

Section: Experimental Approaches To Study Pcg Regulation In Human Cor...mentioning

confidence: 99%

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Polycomb‐mediated gene regulation in human brain development and neurodevelopmental disorders

Bölicke

Albert

2022

Developmental Neurobiology

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The neocortex is considered the seat of higher cognitive function in humans. It develops from a sheet of neural progenitor cells, most of which eventually give rise to neurons. This process of cell fate determination is controlled by precise temporal and spatial gene expression patterns that in turn are affected by epigenetic mechanisms including Polycomb group (PcG) regulation. PcG proteins assemble in multiprotein complexes and catalyze repressive posttranslational histone modifications. Their association with neurodevelopmental disease and various types of cancer of the central nervous system, as well as observations in mouse models, has implicated these epigenetic modifiers in controlling various stages of cortex development. The precise mechanisms conveying PcG‐associated transcriptional repression remain incompletely understood and are an active field of research. PcG activity appears to be highly context‐specific, raising the question of species‐specific differences in the regulation of neural stem and progenitor regulation. In this review, we will discuss our growing understanding of how PcG regulation affects human cortex development, based on studies in murine model systems, but focusing mostly on findings obtained from examining impaired PcG activity in the context of human neurodevelopmental disorders and cancer. Furthermore, we will highlight relevant experimental approaches for functional investigations of PcG regulation in human cortex development.

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Section: Specific Inhibitors Of Pcg Protein Functionmentioning

confidence: 99%

“…To circumvent these disadvantages, specific inhibitors targeting subunits of PcG complexes can be leveraged. As many PcG genes, like EZH2 or PCGF4, are considered oncogenes, research efforts have been invested in the development of efficient and highly specific inhibitors (an extensive list of inhibitors can be found in Wang, Ordonez‐Rubiano, et al., 2021), many of which have already been utilized for functional analysis of PcG regulation (Hojfeldt et al., 2018; Miller et al., 2021; Shukla et al., 2021; van Mierlo et al., 2019; Wang, Alpsoy, et al., 2021). Inhibitor treatment of ESCs could recapitulate findings made in Ezh2 knockout cells, with both H3K27me3 as well as DNA methylation being affected by the depletion of PRC2 (van Mierlo et al., 2019).…”

Section: Experimental Approaches To Study Pcg Regulation In Human Cor...mentioning

confidence: 99%

Section: Experimental Approaches To Study Pcg Regulation In Human Cor...mentioning

confidence: 99%

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Polycomb‐mediated gene regulation in human brain development and neurodevelopmental disorders

Bölicke

Albert

2022

Developmental Neurobiology

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“…Accordingly, inhibition of TGF-beta signaling using small molecules can induce beta-cell replication in aged mice as well as in adult human islets by downregulating Mll1 binding to Ink4a/Arf locus ( Dhawan et al, 2016 ). Direct pharmacological targeting of PcG proteins using small molecules is a rapidly emerging area in onco-therapeutics ( Kreso et al, 2014 ; Shin and Bayarsaihan, 2017 ; Su et al, 2019 ; Shukla et al, 2021 ). Besides being good potential candidates for beta-cell therapies, such small molecules would also allow us to determine causal roles of PcG proteins in beta-cell pathologies.…”

Section: Pcg Regulation In Beta-cells Homeostasismentioning

confidence: 99%

Polycomb Repressive Complexes: Shaping Pancreatic Beta-Cell Destiny in Development and Metabolic Disease

Varghese

Dhawan

2022

Front. Cell Dev. Biol.

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Pancreatic beta-cells secrete the hormone insulin, which is essential for the regulation of systemic glucose homeostasis. Insufficiency of insulin due to loss of functional beta-cells results in diabetes. Epigenetic mechanisms orchestrate the stage-specific transcriptional programs that guide the differentiation, functional maturation, growth, and adaptation of beta-cells in response to growth and metabolic signals throughout life. Primary among these mechanisms is regulation by the Polycomb Repressive Complexes (PRC) that direct gene-expression via histone modifications. PRC dependent histone modifications are pliable and provide a degree of epigenetic plasticity to cellular processes. Their modulation dictates the spatio-temporal control of gene-expression patterns underlying beta-cell homeostasis. Emerging evidence shows that dysregulation of PRC-dependent epigenetic control is also a hallmark of beta-cell failure in diabetes. This minireview focuses on the multifaceted contributions of PRC modules in the specification and maintenance of terminally differentiated beta-cell phenotype, as well as beta-cell growth and adaptation. We discuss the interaction of PRC regulation with different signaling pathways and mechanisms that control functional beta-cell mass. We also highlight recent advances in our understanding of the epigenetic regulation of beta-cell homeostasis through the lens of beta-cell pathologies, namely diabetes and insulinomas, and the translational relevance of these findings. Using high-resolution epigenetic profiling and epigenetic engineering, future work is likely to elucidate the PRC regulome in beta-cell adaptation versus failure in response to metabolic challenges and identify opportunities for therapeutic interventions.

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“…Fragment-based screening and subsequent optimization of molecules that bind to the BMI1/RING1B dimer recently produced the first selective inhibitor of PRC1 RING ubiquitin ligase activity ( 276 ). This inhibitor binds RING1B with 3.6 μM affinity and alters the conformation to block ubiquitination activity.…”

Section: Polycomb Group Protein Modulators: Inhibitors/ Degraders/ Activatorsmentioning

confidence: 99%

Polycomb group proteins in cancer: multifaceted functions and strategies for modulation

et al. 2021

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Polycomb repressive complexes (PRCs) are a heterogenous collection of dozens, if not hundreds, of protein complexes composed of various combinations of subunits. PRCs are transcriptional repressors important for cell-type specificity during development, and as such, are commonly mis-regulated in cancer. PRCs are broadly characterized as PRC1 with histone ubiquitin ligase activity, or PRC2 with histone methyltransferase activity; however, the mechanism by which individual PRCs, particularly the highly diverse set of PRC1s, alter gene expression has not always been clear. Here we review the current understanding of how PRCs act, both individually and together, to establish and maintain gene repression, the biochemical contribution of individual PRC subunits, the mis-regulation of PRC function in different cancers, and the current strategies for modulating PRC activity. Increased mechanistic understanding of PRC function, as well as cancer-specific roles for individual PRC subunits, will uncover better targets and strategies for cancer therapies.

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Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain

Cited by 49 publications

References 60 publications

Polycomb‐mediated gene regulation in human brain development and neurodevelopmental disorders

Polycomb‐mediated gene regulation in human brain development and neurodevelopmental disorders

Polycomb Repressive Complexes: Shaping Pancreatic Beta-Cell Destiny in Development and Metabolic Disease

Polycomb group proteins in cancer: multifaceted functions and strategies for modulation

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