Discovery of a Novel Class of Potent Human Deoxyuridine Triphosphatase Inhibitors Remarkably Enhancing the Antitumor Activity of Thymidylate Synthase Inhibitors

• Published in: Journal of medicinal chemistry 2012-04, Vol.55 (7), p.2970-2980
• Main Authors: Miyahara, Seiji, Miyakoshi, Hitoshi, Yokogawa, Tatsushi, Chong, Khoon Tee, Taguchi, Junko, Muto, Toshiharu, Endoh, Kanji, Yano, Wakako, Wakasa, Takeshi, Ueno, Hiroyuki, Takao, Yayoi, Fujioka, Akio, Hashimoto, Akihiro, Itou, Kenjirou, Yamamura, Keisuke, Nomura, Makoto, Nagasawa, Hideko, Shuto, Satoshi, Fukuoka, Masayoshi
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Drug Synergism; Floxuridine - pharmacology; HeLa Cells; Humans; Mice; Models, Molecular; Neoplasm Transplantation; Protein Conformation; Pyrophosphatases - antagonists & inhibitors; Pyrrolidines - chemical synthesis; Pyrrolidines - pharmacokinetics; Pyrrolidines - pharmacology; Stereoisomerism; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - pharmacokinetics; Sulfonamides - pharmacology; Thymidylate Synthase - antagonists & inhibitors; Transplantation, Heterologous; Uracil - analogs & derivatives; Uracil - chemical synthesis; Uracil - pharmacokinetics; Uracil - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm201628y

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 (IC50 = 100 μM), we developed compound 26, which is the most potent human dUTPase inhibitor (IC50 = 0.021 μM) 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 (EC50 = 0.075 μM) 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.