title: Discovery of highly potent human deoxyuridine triphosphatase inhibitors based on the conformation restriction strategy.
abstract: Human deoxyuridine triphosphatase (dUTPase) inhibition is a promising approach to enhance the efficacy of thymidylate synthase (TS) inhibitor based chemotherapy. In this study, we describe the discovery of a novel class of human dUTPase inhibitors based on the conformation restriction strategy. On the basis of the X-ray cocrystal structure of dUTPase and its inhibitor compound 7, we designed and synthesized two conformation restricted analogues, i.e., compounds 8 and 9. These compounds exhibited increased in vitro potency compared with the parent compound 7. Further structure-activity relationship (SAR) studies identified a compound 43 with the highest in vitro potency (IC(50) = 39 nM, EC(50) = 66 nM). Furthermore, compound 43 had a favorable oral PK profile and exhibited potent antitumor activity in combination with 5-fluorouracil (5-FU) in the MX-1 breast cancer xenograft model. These results suggested that a dUTPase inhibitor may have potential for clinical usage.
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: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D008968:Molecular Conformation; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C575285:N-(1-(3-(cyclopropylmethoxy)phenyl)ethyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pent-3-ene-1-sulfonamide; D013449:Sulfonamides; D014498:Uracil; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase; D005472:Fluorouracil