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

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

  • Mol Cancer Ther. 2018 Aug;17(8):1683-1693. doi: 10.1158/1535-7163.MCT-17-0911.
Wakako Yano  # 1 Tatsushi Yokogawa  # 2 3 Takeshi Wakasa 1 Keisuke Yamamura 1 Akio Fujioka 1 Kunihiro Yoshisue 1 Eiji Matsushima 1 Seiji Miyahara 1 Hitoshi Miyakoshi 1 Junko Taguchi 1 Khoon Tee Chong 1 Yayoi Takao 1 Masayoshi Fukuoka 1 Kenichi Matsuo 2
Affiliations

Affiliations

  • 1 Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
  • 2 Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. matsuken@taiho.co.jp.
  • 3 Business Development Department, Taiho Pharmaceutical Co., Ltd., Kandanishiki-cho, Tokyo, Japan.
  • # Contributed equally.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-124062
    99.76%, dUTPase/DPD Inhibitor