AGF291

AGF291 is a novel 5-substituted pyrrolo[3,2-d]pyrimidine analog developed as a tumor-selective antifolate. It primarily targets mitochondrial one-carbon metabolism by inhibiting serine hydroxymethyltransferase 2 (SHMT2), with secondary inhibitory activity against cytosolic targets such as SHMT1 and enzymes in the de novo purine biosynthesis pathway, specifically AICA ribonucleotide formyltransferase (AICARFTase). The compound is designed to be selectively taken up by cells expressing folate receptor alpha (FRα), which is highly overexpressed in epithelial ovarian cancer (EOC). It also utilizes the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT) for cellular entry. Preclinical studies demonstrate potent activity against various EOC cell lines, including those resistant to cisplatin.