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SHMT inhibitors target serine hydroxymethyltransferase, the enzyme that feeds one-carbon metabolism. Serine hydroxymethyltransferase (SHMT) converts serine and tetrahydrofolate into glycine and 5,10-methylenetetrahydrofolate. Human cells express a cytosolic isoform, SHMT1, and a mitochondrial isoform, SHMT2. SHIN1, a pyrazolopyran inhibitor of both isoforms, was reported in 2017 and revealed a glycine-import defect in diffuse large B-cell lymphoma cells. A 2021 study used the related compound SHIN2 together with methotrexate in T-cell acute lymphoblastic leukemia models. The set lists (+)SHIN2 and (Rac)-SHIN2, together with (+)-SHIN1, SHMT-IN-1 and SHMT-IN-2. Lometrexol, an inhibitor of glycinamide ribonucleotide formyltransferase (GARFT), and the multitargeted antifolate AGF347 act on related folate-dependent steps.
