Structure of 77326-36-4
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Selective and Cell-Active PBRM1 Bromodomain Inhibitors Discovered through NMR Fragment Screening
Shifali Shishodia ; Raymundo Nuñez ; Brayden P. Strohmier ; Karina L. Bursch ; Christopher J. Goetz ; Michael D. Olp , et al.
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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CAS No. : | 77326-36-4 |
Formula : | C7H5FN2 |
M.W : | 136.13 |
SMILES Code : | C1=CC=C(C(=C1N)C#N)F |
MDL No. : | MFCD00015477 |
InChI Key : | IQUNZGOZUJITBJ-UHFFFAOYSA-N |
Pubchem ID : | 522659 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H319 |
Precautionary Statements: | P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 35.52 |
TPSA ? Topological Polar Surface Area: Calculated from |
49.81 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.24 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.61 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.71 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.22 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.5 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.46 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.14 |
Solubility | 0.981 mg/ml ; 0.00721 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.27 |
Solubility | 0.735 mg/ml ; 0.0054 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.37 |
Solubility | 0.578 mg/ml ; 0.00425 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.99 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.31 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | 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. |
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