We report the discovery of a potent and isozyme-selective
MTHFD2
inhibitor, DS18561882 (2). Through investigation of the
substituents on our tricyclic coumarin scaffold (1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one), MTHFD2 inhibitory activity was shown to
be elevated by incorporating an amine moiety at the 8-position and
a methyl group at the 7-position of the initial lead 1. X-ray structure analysis revealed that a key interaction for enhanced
potency was salt bridge formation between the amine moiety and the
diphosphate linker of an NAD+ cofactor. Furthermore, ortho-substituted
sulfonamide in place of benzoic acid of 1 significantly
improved cell permeability and cell-based growth inhibition against
a human breast cancer cell line. The thus-optimized DS18561882 showed
the strongest cell-based activity (GI50 = 140 nM) in the
class, a good oral pharmacokinetic profile, and thereby tumor growth
inhibition in a mouse xenograft model upon oral administration.