AGF347

AGF347 is a **novel pyrrolo[3,2-d]pyrimidine antifolate compound** developed as a multitargeted inhibitor of one-carbon metabolism. It directly targets and inhibits serine hydroxymethyltransferase 2 (SHMT2, mitochondrial) and SHMT1 (cytosolic), as well as two key enzymes in purine biosynthesis: glycinamide ribonucleotide formyltransferase (GARFTase) and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFTase). AGF347 is a folate analog, displaying antitumor activity through disruption of serine catabolism, purine nucleotide biosynthesis, depletion of cellular glutathione, increased reactive oxygen species, and suppression of mammalian target of rapamycin (mTOR) signaling. Unlike classic antifolate drugs, AGF347 also undergoes intracellular polyglutamylation, enhancing its activity within both cytosol and mitochondria. It has shown significant efficacy in vivo in preclinical models of pancreatic cancer and Ewing sarcoma, outperforming gemcitabine in pancreatic cancer xenografts. It is being investigated for its potential application in pancreatic cancer and other malignancies[1][2][3][4].