Abstract: PBRM1 is a subunit of the PBAF chromatin remodeling complex that uniquely contains six bromodomains. PBRM1 can operate as a tumor suppressor or tumor promoter. PBRM1 is a tumor promoter in prostate cancer, contributing to migratory and immunosuppressive phenotypes. Selective chemical probes targeting PBRM1 bromodomains are desired to elucidate the association between aberrant PBRM1 chromatin binding and cancer pathogenesis and the contributions of PBRM1 to immunotherapy. Previous PBRM1 inhibitors unselectively bind SMARCA2 and SMARCA4 bromodomains with nanomolar potency. We used our protein-detected NMR screening pipeline to screen 1968 fragments against the second PBRM1 bromodomain, identifying 17 hits with Kd values from 45 μM to >2 mM. Structure–activity relationship studies on the tightest-binding hit resulted in nanomolar inhibitors with selectivity for PBRM1 over SMARCA2 and SMARCA4. These chemical probes inhibit the association of full-length PBRM1 to acetylated histone peptides and selectively inhibit growth of a PBRM1-dependent prostate cancer cell line.
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With methanol In N,N-dimethyl-formamide at 20℃; for 18 h; Inert atmosphere
NaOMe(25percentwtinMeOH,325μL,1.42mmol,1.1eq.)wasaddedtoasolutionof2-amino-6-fluorobenzonitrile (176 mg, 1.29 mmol, 1.0 eq.) in DMF (1.00 mL) at roomtemperature, and stirred for 18 hours. The solution was concentrated in vacuo and theresidue stirred with H2O (10 mL) to give a beige precipitate. This was filtered underreducedpressure,theresiduedissolvedinEtOAcandconcentratedinvacuo,tituratedwithhexanes before remaining solvent was removed in vacuo giving 2-amino-6-methoxybenzonitrile(158mg,1.07mmol,83percent)asabeigeamorphoussolid;mp143–145°C,lit.136–140°C.13
63%
at 20℃; for 9 h; Heating / reflux
Example 2: Methyl- (2-cyano-3-methoxy-phenyl) sulfonamide; 2.1 : 2-Amino-6-methoxy-benzonitrile A solution of 70 g (0.5 mol) of 2-amino-6-fluoro-benzonitrile (prepared, e. g. according to US 4,504, 660) in 250 ml of N, N-dimethylformamide was initially charged and a solu- tion of 30.6 g (0.55 mol) sodium methoxide in 70 ml of methanol was added dropwise at room temperature while stirring. The mixture was then refluxed for 5 hours under stirring. The completion of the reaction was monitored by TLC. Additional 25 g of so- dium methoxide in 35 ml methanol were added and the reaction mixture was refluxed for additional 4 hours while stirring. The reaction mixture was concentrated under re- duced pressure, the resulting residue was triturated with water, sucked off and the ob- tained solids were dissolved in ethyl acetate. The resulting solution was concentrated in vacuo. The obtained residue was triturated with petroleum ether and sucked off to afford 48 g (63percent of theory) of a brownish solid having a melting point of 143-146°C.
63%
at 20℃; for 9 h; Heating / reflux
Example 2;: N,N-Dimethyl-2-cyano-3-methoxyphenylsulfonamide (Compound No. 2); 2.1 : 2-Amino-6-methoxybenzonitrile; EPO <DP n="33"/>A solution of 70 g (0.5 mol) of 2-amino-6-fluorobenzonitrile (prepared, e.g. according to US 4,504,660) in 250 ml of N,N-dimethylformamide was prepared, and a solution of 30.6 g (0.55 mol) of sodium methoxide in 70 ml of methanol was added dropwise at room temperature while stirring. The mixture was then refluxed for 5 hours with stirring. The completion of the reaction was monitored by TLC. An additional 25 g of sodium methoxide in 35 ml methanol were added and the reaction mixture was refluxed for an additional 4 hours while stirring. The reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with water, filtered off with suction and the solids obtained were dissolved in ethyl acetate. The resulting solution was concen- trated in vacuo. The obtained residue was triturated with petroleum ether and filtered off with suction. Yield: 48 g (63percent of theory) of a brownish solid having a melting point of 143-146°C.
EXAMPLE 36 2'-Cyano-3'-methoxyoxanilic acid ethyl ester. 80/71 2-Amino-6-methoxybenzonitrile (4.67 g, 0.0315 mole) is condensed with 3.88 ml (0.0346 mole) of ethyl oxalylchloride in a manner similar to example 3, giving 5.0 g of the title compound, m.p. 142-145 C., after crystallization from toluene. Elemental Analysis for C12 H12 N2 O4: Calc'd: C, 58.06; H, 4.87; N, 11.29. Found: C, 58.21; H, 4.93; N, 11.02.
EXAMPLE 36 2'-Cyano-3'-methoxyoxanilic acid ethyl ester. 80/71 2-Amino-6-methoxybenzonitrile (4.67 g, 0.0315 mole) is condensed with 3.88 ml (0.0346 mole) of ethyl oxalylchloride in a manner similar to example 3, giving 5.0 g of the title compound, m.p. 142-145C., after crystallization from toluene. Elemental Analysis for C12 H12 N2 O4: Calc'd: C, 58.06; H, 4.87; N, 11.29. Found: C, 58.21; H, 4.93; N, 11.02.
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