Discovery of Highly Potent Human Deoxyuridine Triphosphatase Inhibitors Based on the Conformation Restriction Strategy

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• 作者：Seiji Miyahara ; Hitoshi Miyakoshi ; Tatsushi Yokogawa ; Khoon Tee Chong ; Junko Taguchi ; Toshiharu Muto ; Kanji Endoh ; Wakako Yano ; Takeshi Wakasa ; Hiroyuki Ueno ; Yayoi Takao ; Akio ; Fujioka ; Akihiro Hashimoto ; Kenjirou Itou ; Keisuke Yamamura ; Makoto Nomura ; Hideko Nagasawa ; Satoshi Shuto ; Masayoshi Fukuoka
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：55
• 期：11
• 页码：5483-5496
• 全文大小：552K
• 年卷期：v.55,no.11(June 14, 2012)
• ISSN：1520-4804

文摘

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鈥揳ctivity relationship (SAR) studies identified a compound 43 with the highest in vitro potency (IC₅₀ = 39 nM, EC₅₀ = 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.