DS18561882

DS18561882 is a preclinical, orally available small-molecule inhibitor of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial enzyme in the one‑carbon folate pathway that is overexpressed in many cancers and largely absent from normal adult tissues.[1][3][4] Discovered by Daiichi Sankyo through optimization of a tricyclic coumarin scaffold (1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one), DS18561882 is a highly potent, isozyme-selective substrate-site binder with nanomolar inhibitory activity (IC50 ~6.3 nM) against MTHFD2 and strong tumor growth inhibition in mouse xenograft models upon oral dosing.[1][3][7][11] By blocking MTHFD2-dependent one‑carbon flux and NADPH production, the compound suppresses purine synthesis, perturbs redox homeostasis, increases reactive oxygen species, and reduces proliferation in multiple tumor models, including breast, gastric, and prostate cancer, positioning it as a potential targeted antineoplastic agent.[1][2][3][6][12]