5H4J

Crystal structure of Human dUTPase in complex with N-[(1R)-1-[3-(Cyclopentyloxy)-phenyl]-ethyl]-3-[(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)methoxy]-1-propanesulfonamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.173 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.170 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

TAS-114, a First-in-Class Dual dUTPase/DPD Inhibitor, Demonstrates Potential to Improve Therapeutic Efficacy of Fluoropyrimidine-Based Chemotherapy.

Yano, W.Yokogawa, T.Wakasa, T.Yamamura, K.Fujioka, A.Yoshisue, K.Matsushima, E.Miyahara, S.Miyakoshi, H.Taguchi, J.Chong, K.T.Takao, Y.Fukuoka, M.Matsuo, K.

(2018) Mol Cancer Ther 17: 1683-1693

  • DOI: https://doi.org/10.1158/1535-7163.MCT-17-0911
  • Primary Citation of Related Structures:  
    5H4J

  • PubMed Abstract: 

    5-Fluorouracil (5-FU) is an antimetabolite and exerts antitumor activity via intracellularly and physiologically complicated metabolic pathways. In this study, we designed a novel small molecule inhibitor, TAS-114, which targets the intercellular metabolism of 5-FU to enhance antitumor activity and modulates catabolic pathway to improve the systemic availability of 5-FU. TAS-114 strongly and competitively inhibited deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), a gatekeeper protein preventing aberrant base incorporation into DNA, and enhanced the cytotoxicity of fluoropyrimidines in cancer cells; however, it had little intrinsic activity. In addition, TAS-114 had moderate and reversible inhibitory activity on dihydropyrimidine dehydrogenase (DPD), a catabolizing enzyme of 5-FU. Thus, TAS-114 increased the bioavailability of 5-FU when coadministered with capecitabine in mice, and it significantly improved the therapeutic efficacy of capecitabine by reducing the required dose of the prodrug by dual enzyme inhibition. Enhancement of antitumor efficacy caused by the addition of TAS-114 was retained in the presence of a potent DPD inhibitor containing oral fluoropyrimidine (S-1), indicating that dUTPase inhibition plays a major role in enhancing the antitumor efficacy of fluoropyrimidine-based therapy. In conclusion, TAS-114, a dual dUTPase/DPD inhibitor, demonstrated the potential to improve the therapeutic efficacy of fluoropyrimidine. Dual inhibition of dUTPase and DPD is a novel strategy for the advancement of oral fluoropyrimidine-based chemotherapy for cancer treatment. Mol Cancer Ther; 17(8); 1683-93. ©2018 AACR .


  • Organizational Affiliation

    Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial164Homo sapiensMutation(s): 0 
Gene Names: DUT
EC: 3.6.1.23
UniProt & NIH Common Fund Data Resources
Find proteins for P33316 (Homo sapiens)
Explore P33316 
Go to UniProtKB:  P33316
PHAROS:  P33316
GTEx:  ENSG00000128951 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP33316
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FKM
Query on FKM

Download Ideal Coordinates CCD File 
B [auth A]N-[(1R)-1-[3-(Cyclopentyloxy)-phenyl]-ethyl]-3-[(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)methoxy]-1-propanesulfonamide
C21 H29 N3 O6 S
AMCGLRWKUQPNKD-MRXNPFEDSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
E [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
IMD
Query on IMD

Download Ideal Coordinates CCD File 
D [auth A]IMIDAZOLE
C3 H5 N2
RAXXELZNTBOGNW-UHFFFAOYSA-O
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FKM Binding MOAD:  5H4J Ki: 130 (nM) from 1 assay(s)
BindingDB:  5H4J IC50: min: 60, max: 140 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.173 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.170 
  • Space Group: P 21 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 89.645α = 90
b = 89.645β = 90
c = 89.645γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
CrystalCleardata reduction
CrystalCleardata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-11-01
    Type: Initial release
  • Version 1.1: 2018-09-05
    Changes: Data collection, Database references
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description