N-Benzyl-1-heteroaryl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamides as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1)

Allan, Martin; Manku, Sukhdev; Therrien, Éric; Nguyen, Natalie; Styhler, Sylvia; Robert, Mathieu; Goulet, Anne-Christine; Petschner, Andrea J.; Rahil, Gabi; MacLeod, A. Robert; Déziel, Robert; Besterman, Jeffrey M.; Nguyen, Hannah; Wahhab, Amal

doi:10.1016/j.bmcl.2008.12.075

Cited by 83 publications

(48 citation statements)

References 39 publications

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“…Subsequently, a virtual screen of PRMT1 inhibitors has identified several new compounds including stilbamidine, allantodapsone, and RM65 [38,39]. Recently, potent and selective inhibitors of PRMT4 have been reported [40,41], and these appear to be important first steps toward useful, selective PRMT inhibitors.…”

Section: Reviewmentioning

confidence: 99%

Protein arginine methylation: a new handle on T lymphocytes?

Parry

Ward

2010

Trends in Immunology

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Section: Reviewmentioning

confidence: 99%

Protein arginine methylation: a new handle on T lymphocytes?

Parry

Ward

2010

Trends in Immunology

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“…Based on 23 , structural optimization is performed by replacing the phenyl group with other aromatic ring and exploring more aryl groups for the R group by another lab [81]. From them, 33 and 34 are determined with similar IC 50 .…”

Section: Carm1-specific Inhibitorsmentioning

confidence: 99%

Small Molecule Inhibitors of Protein Arginine Methyltransferases

Qian

et al. 2016

Expert Opinion on Investigational Drugs

106

115

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Introduction Arginine methylation is an abundant posttranslational modification occurring in mammalian cells and catalyzed by protein arginine methyltransferases (PRMTs). Misregulation and aberrant expression of PRMTs are associated with various disease states, notably cancer. PRMTs are prominent therapeutic targets in drug discovery. Areas covered The authors provide an updated review of the research on the development of chemical modulators for PRMTs. Great efforts are seen in screening and designing potent and selective PRMT inhibitors, and a number of micromolar and submicromolar inhibitors have been obtained for key PRMT enzymes such as PRMT1, CARM1, and PRMT5. The authors provide a focus on their chemical structures, mechanism of action, and pharmacological activities. Pros and cons of each type of inhibitors are also discussed. Expert opinion Several key challenging issues exist in PRMT inhibitor discovery. Structural mechanisms of many PRMT inhibitors remain unclear. There lacks consistency in potency data due to divergence of assay methods and conditions. Physiologically relevant cellular assays are warranted. Substantial engagements are needed to investigate pharmacodynamics and pharmacokinetics of the new PRMT inhibitors in pertinent disease models. Discovery and evaluation of potent, isoform-selective, cell-permeable and in vivo-active PRMT modulators will continue to be an active arena of research in years ahead.

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“…63 Similarly, the structurally related compounds from the Methylgene and Bristol-Myers Squibb groups are nanomolar inhibitors of the PRMT CARM1 (also known as PRMT4) that have been shown crystallographically to bind within the arginine channel of this enzyme. 64, 65, 66 …”

Section: Direct Inhibitors Of Pmtsmentioning

confidence: 99%

Targeting genetic alterations in protein methyltransferases for personalized cancer therapeutics

2012

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The human protein methyltransferases (PMTs) constitute a large enzyme class composed of two families, the protein lysine methyltransferases (PKMTs) and the protein arginine methyltransferases (PRMTs). Examples have been reported of both PKMTs and PRMTs that are genetically altered in specific human cancers, and in several cases these alterations have been demonstrated to confer a unique dependence of the cancer cells on PMT enzymatic activity for the tumorigenic phenotype. Examples of such driver alterations in PMTs will be presented together with a review of current efforts towards the discovery and development of small-molecule inhibitors of these enzymes as personalized cancer therapeutics.

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N-Benzyl-1-heteroaryl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamides as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1)

Cited by 83 publications

References 39 publications

Protein arginine methylation: a new handle on T lymphocytes?

Protein arginine methylation: a new handle on T lymphocytes?

Small Molecule Inhibitors of Protein Arginine Methyltransferases

Targeting genetic alterations in protein methyltransferases for personalized cancer therapeutics

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