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

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 23, 2009, Pages 6725-6732

  Therrien, Eric ^a   Larouche, Guillaume ^a   Manku, Sukhdev ^a   Allan, Martin ^a   Nguyen, Natalie ^a   Styhler, Sylvia ^a   Robert, Marie France ^a   Goulet, Anne Christine ^a   Besterman, Jeffrey M ^a   Nguyen, Hannah ^a   Wahhab, Amal ^a  

^a METHYLGENE INC   (Canada)

Author keywords

CARM1 inhibitors; Co activator associated arginine methyltransferase 1; Histone methyltransferase inhibitors; PRMT4 inhibitors

Indexed keywords

COACTIVATOR ASSOCIATED ARGININE METHYLTRANSFERASE 1; DIAMINE DERIVATIVE; METHYLTRANSFERASE; METHYLTRANSFERASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; DRUG CLEARANCE; DRUG DESIGN; DRUG DISTRIBUTION; DRUG HALF LIFE; DRUG PENETRATION; DRUG POTENCY; DRUG STRUCTURE; NONHUMAN; RAT; SUBSTITUTION REACTION;

DIAMINES; DRUG DESIGN; ENZYME INHIBITORS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN-ARGININE N-METHYLTRANSFERASES; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 71749083438     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.09.110     Document Type: Article

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52. 50 >100 μM). The PRMT1 enzyme (N-terminal GST-tagged, human PRMT1 recombinant protein, expressed in E. coli) was purchased from upstate (Cat # 14-474, Lot # 25336). Histone H4 (recombinant protein expressed in E. coli, Cat # 14-412, Lot # 23215, purchased from upstate) was used as the substrate, and the methylation was monitored using tritiated S-Adenosyl-Methionine (SAM) (Amersham Pharmacia Biotech) as a methyl donor. The reactions were performed at 30 °C for a total of 15 min, using enzyme (PRMT1), substrate (histone H4), and co-factor (SAM) in the absence and presence of compound. Assay protocol: 2 μl of the diluted compound was added to a U-Bottom of a PP 96-well plate. PRMT1 enzyme was diluted in a Tris-HCl (pH 9) buffer (to a final enzyme concentration of 0.2 μM) and 10 μl of the cold enzyme solution was immediately added to the compound and allowed to pre-incubate for 10 min at room temperature. A mixture of SAM (20% [3H] SAM) and histone H4 (10 μl) was then added and incubated for 15 min at 30 °C for a final concentration of 3.5 μM histone and 0.2 μM SAM (0.033 mCi/ml). The reaction was stopped by adding 20 μl of SAH for a final concentration of 60 μM and, 10 μl of the quenched reaction is spotted onto P30 Filtermat paper. The Filtermat is washed twice for 15 min with 10% TCA solution and then once for 5 min with 95% ethanol. A wax scintillant is used with the filtermat (Wallac, filtermat A 1450-421) and the radioactivity was read using a Wallac Microbeta counter (CCPM). The SET9 enzyme (N-terminal His-tagged, human SET9 recombinant protein, expressed in E. coli) was purchased from upstate (Cat # 14-469, Lot # 32194). Histone H3 (purchased from upstate) was used as the substrate, and the methylation was monitored using tritiated S-Adenosyl-Methionine (SAM) (Amersham Pharmacia Biotech) as a methyl donor. The reactions were performed at 37 °C for a total of 45 min, using enzyme (SET9), substrate (histone H3), and co-factor (SAM) in the absence and presence of compound. Assay protocol: 2 μl of the diluted compound was added to a U-Bottom of a PP 96-well plate. SET9 enzyme was diluted in a Tris-HCl (pH 9) buffer (to a final enzyme concentration of 0.0005 μg/μl) and 8 μl of the cold enzyme solution was immediately added to the compound and allowed to pre-incubate for 10 min at room temperature. A mixture of SAM (20% [3H] SAM) and histone H3 (10 μl) was then added and incubated for 45 min at 37 °C for a final concentration of 0.06 μg/μl histone and 0.2 μM SAM (0.011 mCi/ml). The reaction was stopped by adding 100 μl of water and transferred to a White Flashplate (Perkin Elmer basic flashplate). The flashplate was washed twice with 10% TCA. The dry plate was read using a Wallac Microbeta counter (CCPM).