Allosteric Modulation of Protein Arginine Methyltransferase 5 (PRMT5)

Palte, R.L.; Schneider, Sebastian E; Altman, Michael D.; Hayes, Robert P.; Kawamura, Shuhei; Lacey, Brian M.; Mansueto, My Sam; Reutershan, Michael H.; Siliphaivanh, Phieng; Sondey, Christopher; Xu, Haiyan; Xu, Zangwei; Ye, Yingchun; Machacek, Michelle R.

doi:10.1021/acsmedchemlett.9b00525

Cited by 31 publications

(32 citation statements)

References 22 publications

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“…25 In addition, EPZ020411 27 was reported as a PRMT6 inhibitor with limited selectivity. Here, we report the first highly selective and cell-active allosteric inhibitor of PRMT6, SGC6870, which is one of only few PRMT allosteric inhibitors including our previously reported PRMT3 allosteric inhibitor, SGC707, 13 and a recently reported PRMT5 allosteric inhibitor 28 . We also developed SGC6870N, which is the enantiomer of SGC6870 but is inactive for PRMT6, as a negative control of SGC6870 for chemical biology studies.…”

mentioning

confidence: 87%

A First-in-class, Highly Selective and Cell-active Allosteric Inhibitor of Protein Arginine Methyltransferase 6 (PRMT6)

Shen¹,

Li²,

Szewczyk³

et al. 2020

Preprint

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PRMT6 catalyzes monomethylation and asymmetric dimethylation of arginine residues in various proteins, plays important roles in biological processes and is associated with multiple cancers. While there are several reported PRMT6 inhibitors, a highly selective PRMT6 inhibitor has not been reported to date. Furthermore, allosteric inhibitors of protein methyltransferases are rare. Here we report the discovery and characterization of a first-in-class, highly selective allosteric inhibitor of PRMT6, SGC6870. SGC6870 is a potent PRMT6 inhibitor (IC50 = 77 ± 6 nM) with outstanding selectivity for PRMT6 over a broad panel of other methyltransferases and non-epigenetic targets. Notably, the crystal structure of the PRMT6–SGC6870 complex and kinetic studies revealed SGC6870 binds a unique, induced allosteric pocket. Additionally, SGC6870 engages PRMT6 and potently inhibits its methyltransferase activity in cells. Moreover, SGC6870’s enantiomer, SGC6870N, is inactive against PRMT6 and can be utilized as a negative control. Collectively, SGC6870 is a well-characterized PRMT6 chemical probe and valuable tool for further investigating PRMT6 functions in health and disease.

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confidence: 87%

A First-in-class, Highly Selective and Cell-active Allosteric Inhibitor of Protein Arginine Methyltransferase 6 (PRMT6)

Shen¹,

Li²,

Szewczyk³

et al. 2020

Preprint

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“…When tested in vivo, the drug had an IC 50 of 25 nM, measured by the levels of methylated SmBB. Recently, a novel allosteric inhibitor of PRMT5 has been reported, which leads to occlusion of both the SAM and substrate-binding sites through displacement of the loop ELLGSFADNEL spanning PRMT5 residues 435–445 (Palte et al 2020 ). The question of whether the combination of Type I and Type II inhibitors would synergise against tumour cells is obvious and has recently been addressed by several research groups (Fedoriw et al 2019 ; Fong et al 2019 ; Gao et al 2019 ).…”

Section: Regulation Of Arginine Methylationmentioning

confidence: 99%

Arginine methylation: the promise of a ‘silver bullet’ for brain tumours?

et al. 2021

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Despite intense research efforts, our pharmaceutical repertoire against high-grade brain tumours has not been able to increase patient survival for a decade and life expectancy remains at less than 16 months after diagnosis, on average. Inhibitors of protein arginine methyltransferases (PRMTs) have been developed and investigated over the past 15 years and have now entered oncology clinical trials, including for brain tumours. This review collates recent advances in the understanding of the role of PRMTs and arginine methylation in brain tumours. We provide an up-to-date literature review on the mechanisms for PRMT regulation. These include endogenous modulators such as alternative splicing, miRNA, post-translational modifications and PRMT–protein interactions, and synthetic inhibitors. We discuss the relevance of PRMTs in brain tumours with a particular focus on PRMT1, -2, -5 and -8. Finally, we include a future perspective where we discuss possible routes for further research on arginine methylation and on the use of PRMT inhibitors in the context of brain tumours.

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“…Therefore, although low MTA and PRMT5 inhibitor concentration showed synergistic enhanced PRMT5 inhibition, the synergy is markedly attenuated at a high concentration of either MTA or PRMT5 inhibitor [50]. Newer generations of PRMT5 inhibitors are designed to escape this competition, so it remains to be seen if MTAP status may still be of relevance [157,158].…”

Section: Potential Selective Predictive Response Biomarkersmentioning

confidence: 99%

PRMT5: An Emerging Target for Pancreatic Adenocarcinoma

Lee

Grimmond

McArthur

et al. 2021

Cancers

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The overall survival of pancreatic ductal adenocarcinoma (PDAC) remains poor and its incidence is rising. Targetable mutations in PDAC are rare, thus novel therapeutic approaches are needed. Protein arginine methyltransferase 5 (PRMT5) overexpression is associated with worse survival and inhibition of PRMT5 results in decreased cancer growth across multiple cancers, including PDAC. Emerging evidence also suggests that altered RNA processing is a driver in PDAC tumorigenesis and creates a partial dependency on this process. PRMT5 inhibition induces altered splicing and this vulnerability can be exploited as a novel therapeutic approach. Three possible biological pathways underpinning the action of PRMT5 inhibitors are discussed; c-Myc regulation appears central to its action in the PDAC setting. Whilst homozygous MTAP deletion and symmetrical dimethylation levels are associated with increased sensitivity to PRMT5 inhibition, neither measure robustly predicts its growth inhibitory response. The immunomodulatory effect of PRMT5 inhibitors on the tumour microenvironment will also be discussed, based on emerging evidence that PDAC stroma has a significant bearing on disease behaviour and response to therapy. Lastly, with the above caveats in mind, current knowledge gaps and the implications and rationales for PRMT5 inhibitor development in PDAC will be explored.

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Allosteric Modulation of Protein Arginine Methyltransferase 5 (PRMT5)

Cited by 31 publications

References 22 publications

A First-in-class, Highly Selective and Cell-active Allosteric Inhibitor of Protein Arginine Methyltransferase 6 (PRMT6)

A First-in-class, Highly Selective and Cell-active Allosteric Inhibitor of Protein Arginine Methyltransferase 6 (PRMT6)

Arginine methylation: the promise of a ‘silver bullet’ for brain tumours?

PRMT5: An Emerging Target for Pancreatic Adenocarcinoma

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