Tsukuba Research Center, Taiho Pharmaceutical Co. Ltd., Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.
J Med Chem. 2012 Apr 12;55(7):2970-80. doi: 10.1021/jm201628y. Epub 2012 Mar 26.
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.
抑制人脱氧尿嘧啶三磷酸酶（dUTPase）已被确定为提高基于 5-氟尿嘧啶（5-FU）的化疗疗效的一种很有前途的方法。本研究描述了一类基于尿嘧啶衍生物的结构-活性关系（SAR）研究的新型 dUTPase 抑制剂的开发。从弱抑制剂 7（IC50=100μM）出发，我们开发了化合物 26，这是迄今为止报道的最有效的人 dUTPase 抑制剂（IC50=0.021μM）。化合物 26 不仅显著增强了 5-氟-2'-脱氧尿苷（FdUrd）对 HeLa S3 细胞的体外生长抑制活性（EC50=0.075μM），而且当与 5-FU 连续输注口服给药时，对 MX-1 乳腺癌异种移植模型在体内也显示出强大的抗肿瘤活性。这是 dUTPase 抑制剂增强 TS 抑制剂抗肿瘤活性的首例体内证据。基于这些发现，可以得出结论，化合物 26 是一种很有前途的临床开发候选药物。
