Abstract: Here, we report the fragment-based drug discovery of potent and selective fragments that disrupt the Spire2-FMN2 but not the Spire1-FMN2 interaction. Hit fragments were identified in a differential scanning fluorimetry-based screen of an inhouse library of 755 compounds and subsequently validated in multiple orthogonal biophys. assays, including fluorescence polarization, microscale thermophoresis, and 1H-15N HSQC NMR. Extensive structure-activity relationships combined with mol. docking followed by chem. optimization led to the discovery of compound 13, which exhibits micromolar potency and high ligand efficiency (LE = 0.38). Therefore, this fragment represents a validated starting point for the future development of selective chem. probes targeting the Spire2-FMN2 interaction.
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ethyl 3-((8-chloroquinolin-4-yl)amino)-2-nitrobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate; palladium diacetate; XPhos; In toluene; at 90℃; for 16.0h;
Palladium (II) acetate (103 mg, 0.46 mmol) was added to a mixture of <strong>[193014-01-6]ethyl 3-amino-2-nitrobenzoate</strong> (1.2 g, 5.7 mmol), 4,8-dichloroquinoline (1.24 g, 6.3 mmol), dicyclohexyl(2?,4?,6?-triisopropyl-[1,1?-biphenyl]-2-yl)phosphine (653 mg, 1.37 mmol), and potassium phosphate (2.42 g, 11.4 mmol) in toluene (23 mL). The resultant was degassed and stirred at 90 C. for 16 hours. The reaction mixture was cooled to room temperature and dry loaded onto silica gel and purified eluting with 0 to 100% ethyl acetate in hexanes to afford the title compound as a brown solid. ES/MS m/z=372.1 (M+H).
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