Benzo[d]imidazole inhibitors of Coactivator Associated Arginine Methyltransferase 1 (CARM1)—Hit to Lead studies

Wan, Honghe; Huynh, Tram; Pang, Suhong; Geng, Jieping; Vaccaro, Wayne; Poss, Michael A.; Trainor, George L.; Lorenzi, Matthew V.; Gottardis, Marco M.; Jayaraman, Lata; Purandare, Ashok V.

doi:10.1016/j.bmcl.2009.07.040

Cited by 55 publications

(43 citation statements)

References 20 publications

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“…167 Subsequent optimization of the initial hit compounds resulted in nanomolar inhibitors such as the indole derivative 40 and the pyrazole derivative 41 , which possess IC 50 values of 30 and 27 nM, respectively (Figure 42). 168 Interestingly, both of these inhibitors bind to the substrate arginine-binding cavity of PRMT4 and require the presence of bound cofactor SAH (Figure 42).…”

Section: Histone Arginine Methylationmentioning

confidence: 99%

Chemical Biology of Protein Arginine Modifications in Epigenetic Regulation

Fuhrmann

Clancy²,

Thompson³

2015

Chem. Rev.

228

340

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Section: Histone Arginine Methylationmentioning

confidence: 99%

Chemical Biology of Protein Arginine Modifications in Epigenetic Regulation

Fuhrmann

Clancy²,

Thompson³

2015

Chem. Rev.

228

340

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“…16−18 Substrate-based inhibitors have particular value for obtaining cocrystal structures of the enzyme–substrate complex, thus being useful molecular tools for understanding substrate recognition mechanism. On the other hand, a number of small molecule PRMT inhibitors have been reported such as AMI-1, 19 stilbamidine and allantodapsone, 20 RM65, 21 pyrazoles, 22−25 benzo[ d ]imidazoles, 26 NS-1, 27 among others. 15,28−33 It should be cautioned that some of these compounds, e.g., AMI-1, NS-1, and A36, most likely target the histone substrate rather than the PRMT1 enzyme.…”

Section: Introductionmentioning

confidence: 99%

Diamidine Compounds for Selective Inhibition of Protein Arginine Methyltransferase 1

et al. 2014

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Protein arginine methylation is a posttranslational modification critical for a variety of biological processes. Misregulation of protein arginine methyltransferases (PRMTs) has been linked to many pathological conditions. Most current PRMT inhibitors display limited specificity and selectivity, indiscriminately targeting many methyltransferase enzymes that use S-adenosyl-l-methionine as a cofactor. Here we report diamidine compounds for specific inhibition of PRMT1, the primary type I enzyme. Docking, molecular dynamics, and MM/PBSA analysis together with biochemical assays were conducted to understand the binding modes of these inhibitors and the molecular basis of selective inhibition for PRMT1. Our data suggest that 2,5-bis(4-amidinophenyl)furan (1, furamidine, DB75), one leading inhibitor, targets the enzyme active site and is primarily competitive with the substrate and noncompetitive toward the cofactor. Furthermore, cellular studies revealed that 1 is cell membrane permeable and effectively inhibits intracellular PRMT1 activity and blocks cell proliferation in leukemia cell lines with different genetic lesions.

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“…Another structural class of CARM1 inhibitors (Benzo[ d ]imidazole inhibitors) represented by compounds 41 and 42 is identified [85] from screening campaign by the same lab who discovered 23 – 32 . Removing or modification of the 2-methylaminoethyl group of 41 results complete loss of the activity while substitution of the middle benzimidazole seems tolerable.…”

Section: Carm1-specific Inhibitorsmentioning

confidence: 99%

Small Molecule Inhibitors of Protein Arginine Methyltransferases

Qian

et al. 2016

Expert Opinion on Investigational Drugs

105

109

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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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Benzo[d]imidazole inhibitors of Coactivator Associated Arginine Methyltransferase 1 (CARM1)—Hit to Lead studies

Cited by 55 publications

References 20 publications

Chemical Biology of Protein Arginine Modifications in Epigenetic Regulation

Chemical Biology of Protein Arginine Modifications in Epigenetic Regulation

Diamidine Compounds for Selective Inhibition of Protein Arginine Methyltransferase 1

Small Molecule Inhibitors of Protein Arginine Methyltransferases

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