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Human GAR transformylase in complex with GAR substrate and AGF291 inhibitor
Structural highlights
FunctionPublication Abstract from PubMedMultitargeted agents provide tumor selectivity with reduced drug resistance and dose-limiting toxicities. We previously described the multitargeted 6-substituted pyrrolo[3,2-d]pyrimidine antifolate 1 with activity against early- and late-stage pancreatic tumors with limited tumor selectivity. Structure-based design with our human serine hydroxymethyl transferase (SHMT) 2 and glycinamide ribonucleotide formyltransferase (GARFTase) structures, and published X-ray crystal structures of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC), SHMT1, and folate receptor (FR) alpha and beta afforded 11 analogues. Multitargeted inhibition and selective tumor transport were designed by providing promiscuous conformational flexibility in the molecules. Metabolite rescue identified mitochondrial C1 metabolism along with de novo purine biosynthesis as the targeted pathways. We identified analogues with tumor-selective transport via FRs and increased SHMT2, SHMT1, and GARFTase inhibition (28-, 21-, and 11-fold, respectively) compared to 1. These multitargeted agents represent an exciting new structural motif for targeted cancer therapy with substantial advantages of selectivity and potency over clinically used antifolates. Structure-Based Design of Transport-Specific Multitargeted One-Carbon Metabolism Inhibitors in Cytosol and Mitochondria.,Nayeen MJ, Katinas JM, Magdum T, Shah K, Wong JE, O'Connor CE, Fifer AN, Wallace-Povirk A, Hou Z, Matherly LH, Dann CE 3rd, Gangjee A J Med Chem. 2023 Aug 24;66(16):11294-11323. doi: 10.1021/acs.jmedchem.3c00763. , Epub 2023 Aug 15. PMID:37582241[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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