1,2-Diamines as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1)

Therrien, Éric; Larouche, Guillaume; Manku, Sukhdev; Allan, Martin; Nguyen, Natalie; Styhler, Sylvia; Robert, Mathieu; Goulet, Anne-Christine; Besterman, Jeffrey M.; Nguyen, Hannah; Wahhab, Amal

doi:10.1016/j.bmcl.2009.09.110

Cited by 45 publications

(41 citation statements)

References 47 publications

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“…However, as (2) shows only modest permeability, Purandare and colleagues developed the CARM1 inhibitors (3) and (4), which show high permeability and stability in in vitro assays, through SAR development and optimization [39]. In addition, Wahhab and colleagues replaced the core phenyl ring or (S)-alanine benzylamide moiety of (2) with other heterocyclic rings or an N 1 -benzyl-N 2 -methylethane-1,2-diamine unit, respectively, and identified novel inhibitors ((5) [40]; (6) [41]) of CARM1. Although (5) and (6) show similar potency as (2) along with good pharmacokinetic properties, they do not show measurable cellular activities.…”

Section: Regulation Of Prmts Activitymentioning

confidence: 99%

“…Fourth, as we described above, small molecules that specifically regulate the activity of PRMTs have been extensively searched for therapeutic purposes. However, since these small molecules have been shown to only regulate the enzyme activity of PRMTs in vitro, their efficacy needs to be improved for their in vivo application [40,41]. Recent studies showed that PRMTs are regulated by their own binding partners or by posttranslational modifications.…”

Section: Expert Opinion and Conclusionmentioning

confidence: 99%

“…After several rounds of filtration, they isolated nine inhibitors of hPRMT1 with IC 50 values ranging from 13 to 37 µM, which indicates that the inhibitors were much less effective than AMI-1 or allantodapsone. More drug-like inhibitors for CARM1 have been identified by systematic optimization processes ( Figure 4) [38][39][40][41]. Initially, a pyrazole amide derivative (1) was identified as a 'hit' with modest inhibitory activity (IC 50 = 1.8 µM) from a high throughput screening [38].…”

Section: Regulation Of Prmts Activitymentioning

confidence: 99%

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Protein arginine methyltransferases (PRMTs) as therapeutic targets

Cha

Jho

2012

Expert Opinion on Therapeutic Targets

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The roles of PRMTs have been fairly well established, but further studies are required to determine how PRMTs are regulated by cellular signaling pathways in vivo. Since the usage of adult stem cells is under intense scrutiny by society, identification of the roles of PRMTs in adult stem cells is expected in the near future. Although small molecules specific to PRMTs with high potency in vitro have been identified, development of small molecules that can regulate the activity of PRMTs in vivo is urgently required for therapeutic purposes.

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Section: Regulation Of Prmts Activitymentioning

confidence: 99%

Section: Expert Opinion and Conclusionmentioning

confidence: 99%

Section: Regulation Of Prmts Activitymentioning

confidence: 99%

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Protein arginine methyltransferases (PRMTs) as therapeutic targets

Cha

Jho

2012

Expert Opinion on Therapeutic Targets

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“…However, no inhibition was observed for cellular methylation of H3R26 by the treatment of 34 at 5 μM for 48 h. In addition, 34 failed to show any significant activity in the hormone-dependent assays (IC 50 > 10 μM), which is probably due to the poor cell permeability considering their structural resemblance to 23 . Envisaging that the alanine group (south end of 23) might be the cause, the lab then sought to improve the quality by replacing the alanine with other groups which generated compound 35 with a N 2 -methyl-1,2-diamine group in south end showing IC 50 of 0.2 μM [84]. Further modification of the R group yielded compound 36 – 39 (IC 50 = 0.32 – 0.9 μM).…”

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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“…These inhibitors displayed selectivity for CARM1 over PRMT1 and PRMT3 while the selectivity over other PRMTs was not reported (Figure 1). 20–23 We have recently reported a type I PRMT chemical probe, MS023 ( 3 ), which is potent against all type I PRMTs, but inactive against type II and type III PRMTs as well as other methyltransferases. 24 A series of adenosine-based CARM1 inhibitors with high potency and selectivity over PRMT1 and PRMT6 was also published.…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of selective, small molecule inhibitors of coactivator-associated arginine methyltransferase 1 (CARM1)

et al. 2016

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Coactivator-associated arginine methyltransferase 1 (CARM1) is a type I protein arginine methyltransferase (PRMT) that catalyzes the conversion of arginine into monomethylarginine (MMA) and further into asymmetric dimethylarginine (ADMA). CARM1 methylates histone 3 arginines 17 and 26, as well as numerous non-histone proteins including CBP/p300, SRC-3, NCOA2, PABP1, and SAP49, while also functioning as a coactivator for various proteins that have been linked to cancer such as p53, NF-κβ, β-catenin, E2F1 and steroid hormone receptor ERα. As a result, CARM1 is involved in transcriptional activation, cellular differentiation, cell cycle progression, RNA splicing and DNA damage response. It has been associated with several human cancers including breast, colon, prostate and lung cancers and thus, is a potential oncological target. Herein, we present the design and synthesis of a series of CARM1 inhibitors. Based on a fragment hit, we discovered compound 9 as a potent inhibitor that displayed selectivity for CARM1 over other PRMTs.

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1,2-Diamines as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1)

Cited by 45 publications

References 47 publications

Protein arginine methyltransferases (PRMTs) as therapeutic targets

Protein arginine methyltransferases (PRMTs) as therapeutic targets

Small Molecule Inhibitors of Protein Arginine Methyltransferases

Design and synthesis of selective, small molecule inhibitors of coactivator-associated arginine methyltransferase 1 (CARM1)

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