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

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. .

CRISPR/Cas9-mediated knock-out of dUTPase in mice leads to early embryonic lethality

“…Still, the dUTPase silenced cell lines showed increased sensitivity towards inhibitors of de novo thymidylate biosynthesis. These findings corroborated the clinical significance of dUTPase inhibition in anticancer chemotherapies 30,31,32 . To our best knowledge, knock-out studies on dUTPases have not yet been published for any mammalian species.…”

Structural comparisons of host and African swine fever virus dUTPases reveal new clues for inhibitor development

“…(iii) adding groups on the butyl of compound 1 to improve the affinity with the active sites. According to previous studies on dUTPase inhibitors, a flexible inhibitor (containing a flexible linker moiety) could be a promising agent to increase the affinity between inhibitors and target dUTPases (34,35), because a flexible inhibitor could more easily adopt a conformation to minimize entropic loss (34). These observations should be considered in the development of inhibitors against ASFV dUTPase without affect swine dUTPase.…”

A randomized, phase 2 study of deoxyuridine triphosphatase inhibitor, TAS-114, in combination with S-1 versus S-1 alone in patients with advanced non-small-cell lung cancer

“…TAS-114 inhibits the conversion of deoxyuridine triphosphate ( d U T P) an d 5-f l u oro -d U T P ( F dU T P ) in t o the i r monophosphate forms. TAS-114 itself does not have antitumor activity; however, when it is combined with 5-FU derivatives, it can increase the amount of FdUTP in the tumor for selective incorporation into DNA, thus enhancing the antitumor effect [7,8].…”