5uz0

Crystal structure of AICARFT bound to an antifolate

spinqualitylabelsall models 5uz0, resolution 1.79Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5uz0 is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 8US, AMZ, MG Related: 5uy8 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [PUR9_HUMAN] Defects in ATIC are the cause of AICAR transformylase/IMP cyclohydrolase deficiency (AICAR) [MIM:608688]. A neurologically devastating inborn error of purine biosynthesis. Patients excrete massive amounts of AICA-riboside in the urine and accumulate AICA-ribotide and its derivatives in erythrocytes and fibroblasts. AICAR causes profound mental retardation, epilepsy, dysmorphic features and congenital blindness. Function [PUR9_HUMAN] Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis. Publication Abstract from PubMed A hallmark of cancer is unbridled proliferation that can result in increased demand for de novo synthesis of purine and pyrimidine bases required for DNA and RNA biosynthesis. These synthetic pathways are frequently upregulated in cancer and involve various folate-dependent enzymes. Antifolates have a proven record as clinically used oncolytic agents. Our recent research efforts have produced LSN 3213128 (compound 28a), a novel, selective, nonclassical, orally bioavailable antifolate with potent and specific inhibitory activity for aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFT), an enzyme in the purine biosynthetic pathway. Inhibition of AICARFT with compound 28a results in dramatic elevation of 5-aminoimidazole 4-carboxamide ribonucleotide (ZMP) and growth inhibition in NCI-H460 and MDA-MB-231met2 cancer cell lines. Treatment with this inhibitor in a murine based xenograft model of triple negative breast cancer (TNBC) resulted in tumor growth inhibition. Discovery of N-(6-Fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)-5-[(3R)-3-hydroxypyrrolidin-1-yl]t hiophene-2-sulfonamide (LSN 3213128), a Potent and Selective Nonclassical Antifolate Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase (AICARFT) Inhibitor Effective at Tumor Suppression in a Cancer Xenograft Model.,Fales KR, Njoroge FG, Brooks HB, Thibodeaux S, Torrado A, Si C, Toth JL, Mc Cowan JR, Roth KD, Thrasher KJ, Frimpong K, Lee MR, Dally RD, Shepherd TA, Durham TB, Margolis BJ, Wu Z, Wang Y, Atwell S, Wang J, Hui YH, Meier TI, Konicek SA, Geeganage S J Med Chem. 2017 Dec 14;60(23):9599-9616. doi: 10.1021/acs.jmedchem.7b01046. Epub, 2017 Nov 9. PMID:29072452 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Bifunctional purine biosynthesis protein PURH

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