8FDY

Human GAR transformylase in complex with GAR substrate and AGF132 inhibitor

Summary for 8FDY

• Entry DOI: 10.2210/pdb8fdy/pdb
• Descriptor: Phosphoribosylglycinamide formyltransferase, GLYCINAMIDE RIBONUCLEOTIDE, N-{5-[4-(2-amino-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-6-yl)butyl]pyridine-2-carbonyl}-L-glutamic acid, ... (4 entities in total)
• Functional Keywords: garftas, purine biosynthesis, monomer, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 23567.80

Authors

Wong-Roushar, J.,Dann III, C.E. (deposition date: 2022-12-05, release date: 2023-05-10, Last modification date: 2024-05-22)

Primary citation

Tong, N.,Wong-Roushar, J.,Wallace-Povirk, A.,Shah, Y.,Nyman, M.C.,Katinas, J.M.,Schneider, M.,O'Connor, C.,Bao, X.,Kim, S.,Li, J.,Hou, Z.,Matherly, L.H.,Dann 3rd, C.E.,Gangjee, A.
Multitargeted 6-Substituted Thieno[2,3- d ]pyrimidines as Folate Receptor-Selective Anticancer Agents that Inhibit Cytosolic and Mitochondrial One-Carbon Metabolism.
Acs Pharmacol Transl Sci, 6:748-770, 2023

PubMed Abstract: Multitargeted agents with tumor selectivity result in reduced drug resistance and dose-limiting toxicities. We report 6-substituted thieno[2,3-]pyrimidine compounds (-) with pyridine (, ), fluorine-substituted pyridine (), phenyl (, ), and thiophene side chains (, ), for comparison with unsubstituted phenyl (, ) and thiophene side chain (, ) containing thieno[2,3-]pyrimidine compounds. Compounds - inhibited proliferation of Chinese hamster ovary cells (CHO) expressing folate receptors (FRs) α or β but not the reduced folate carrier (RFC); modest inhibition of CHO cells expressing the proton-coupled folate transporter (PCFT) by , , , and was observed. Replacement of the side-chain 1',4'-phenyl ring with 2',5'-pyridyl, or 2',5'-pyridyl with a fluorine insertion ortho to l-glutamate resulted in increased potency toward FR-expressing CHO cells. Toward KB tumor cells, - were highly active (IC's from 2.11 to 7.19 nM). By metabolite rescue in KB cells and enzyme assays, purine biosynthesis was identified as a targeted pathway (at 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFTase) and glycinamide ribonucleotide formyltransferase (GARFTase)). Compound was 17- to 882-fold more potent than previously reported compounds , , and against GARFTase. By targeted metabolomics and metabolite rescue, , , and also inhibited mitochondrial serine hydroxymethyl transferase 2 (SHMT2); enzyme assays confirmed inhibition of SHMT2. X-ray crystallographic structures were obtained for , , , and with human GARFTase. This series affords an exciting new structural platform for potent multitargeted antitumor agents with FR transport selectivity.

PubMed: 37200803
DOI: 10.1021/acsptsci.3c00020

Experimental method

X-RAY DIFFRACTION (2.06 Å)