- Discovery of highly potent human deoxyuridine triphosphatase inhibitors based on the conformation restriction strategy
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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 (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.
- 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
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p. 5483 - 5496
(2012/08/28)
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