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

Summary for 5H4J

• Entry DOI: 10.2210/pdb5h4j/pdb
• Descriptor: Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial, N-[(1R)-1-[3-(Cyclopentyloxy)-phenyl]-ethyl]-3-[(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)methoxy]-1-propanesulfonamide, ZINC ION, ... (6 entities in total)
• Functional Keywords: hydrolase, hydrolase inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 18435.23

Authors

Chong, K.T.,Miyahara, S.,Miyakoshi, H.,Fukuoka, M. (deposition date: 2016-11-01, release date: 2017-11-01, Last modification date: 2023-11-08)

Primary citation

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.
TAS-114, a First-in-Class Dual dUTPase/DPD Inhibitor, Demonstrates Potential to Improve Therapeutic Efficacy of Fluoropyrimidine-Based Chemotherapy.
Mol. Cancer Ther., 17:1683-1693, 2018

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. .

PubMed: 29748212
DOI: 10.1158/1535-7163.MCT-17-0911

Experimental method

X-RAY DIFFRACTION (1.8 Å)