AGF359

AGF359 is a novel 5-substituted pyrrolo[3,2-d]pyrimidine analog designed to target mitochondrial and cytosolic one-carbon (C1) metabolism. It primarily acts as an inhibitor of serine hydroxymethyltransferase 2 (SHMT2) in the mitochondria, while also providing secondary inhibition of cytosolic targets including serine hydroxymethyltransferase 1 (SHMT1) and enzymes in the de novo purine biosynthesis pathway, such as 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFTase). The compound is engineered for tumor-selective delivery via the folate receptor alpha (FRα), which is frequently overexpressed in epithelial ovarian cancers (EOC). In preclinical studies, AGF359 has demonstrated nanomolar potency against cisplatin-resistant EOC cell lines, inducing apoptosis through mechanisms involving glycine depletion and the perturbation of glutathione pools. It was developed through collaborative research at Wayne State University and Duquesne University.