3arn

Human dUTPase in complex with novel uracil derivative

spinqualitylabelsall models 3arn, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3arn is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: MG, MSJ Related: 3ara, 2hqu Activity: dUTP diphosphatase, with EC number 3.6.1.23 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [DUT_HUMAN] This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA. Publication Abstract from PubMed Inhibition of human deoxyuridine triphosphatase (dUTPase) has been identified as a promising approach to enhance the efficacy of 5-fluorouracil (5-FU)-based chemotherapy. This study describes the development of a novel class of dUTPase inhibitors based on the structure-activity relationship (SAR) studies of uracil derivatives. Starting from the weak inhibitor 7 (IC(50) = 100 muM), we developed compound 26, which is the most potent human dUTPase inhibitor (IC(50) = 0.021 muM) reported to date. Not only does compound 26 significantly enhance the growth inhibition activity of 5-fluoro-2'-deoxyuridine (FdUrd) against HeLa S3 cells in vitro (EC(50) = 0.075 muM) but also shows robust antitumor activity against MX-1 breast cancer xenograft model in mice when administered orally with a continuous infusion of 5-FU. This is the first in vivo evidence that human dUTPase inhibitors enhance the antitumor activity of TS inhibitors. On the basis of these findings, it was concluded that compound 26 is a promising candidate for clinical development. Discovery of a novel class of potent human deoxyuridine triphosphatase inhibitors remarkably enhancing the antitumor activity of thymidylate synthase inhibitors.,Miyahara S, Miyakoshi H, Yokogawa T, Chong KT, Taguchi J, Muto T, Endoh K, Yano W, Wakasa T, Ueno H, Takao Y, Fujioka A, Hashimoto A, Itou K, Yamamura K, Nomura M, Nagasawa H, Shuto S, Fukuoka M J Med Chem. 2012 Apr 12;55(7):2970-80. Epub 2012 Mar 26. PMID:22339362 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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