title: Discovery of a novel class of potent human deoxyuridine triphosphatase inhibitors remarkably enhancing the antitumor activity of thymidylate synthase inhibitors.
abstract: 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 (IC(50) = 100 μM), we developed compound 26, which is the most potent human dUTPase inhibitor (IC(50) = 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 (EC(50) = 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.
authors.affiliation: Tsukuba Research Center, Taiho Pharmaceutical Co. Ltd., Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Miyahara
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Miyakoshi
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Yokogawa
authors.forename: Khoon Tee
authors.initials: KT
authors.lastname: Chong
authors.forename: Junko
authors.initials: J
authors.lastname: Taguchi
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Muto
authors.forename: Kanji
authors.initials: K
authors.lastname: Endoh
authors.forename: Wakako
authors.initials: W
authors.lastname: Yano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Wakasa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ueno
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Takao
authors.forename: Akio
authors.initials: A
authors.lastname: Fujioka
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hashimoto
authors.forename: Kenjirou
authors.initials: K
authors.lastname: Itou
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yamamura
authors.forename: Makoto
authors.initials: M
authors.lastname: Nomura
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Fukuoka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005467:Floxuridine / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011487:Protein Conformation; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014183:Transplantation, Heterologous; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C574630:N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)-3-((2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)propane-1-sulfonamide; D011759:Pyrrolidines; D013449:Sulfonamides; D005467:Floxuridine; D014498:Uracil; D013940:Thymidylate Synthase; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase