Document Report Card

ID: ALA2146384

Journal: J Med Chem

Title: Discovery of highly potent human deoxyuridine triphosphatase inhibitors based on the conformation restriction strategy.

Authors: Miyahara S, Miyakoshi H, Yokogawa T, Chong KT, Taguchi J, Muto T, Endoh K, Yano W, Wakasa T, Ueno H, Takao Y, Fujioka A, Hashimoto A, Itou K, Yamamura K, Nomura M, Nagasawa H, Shuto S, Fukuoka M.

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.

CiteXplore: 22607122

DOI: 10.1021/jm300416h