Design, synthesis, and evaluation of potent and selective benzoyleneurea-based inhibitors of protein geranylgeranyltransferase-1

被引：17
作者：
Carrico, D
Blaskovich, MA
Bucher, CJ
Sebti, SM
Hamilton, AD
机构：
[1] Yale Univ, Dept Chem, New Haven, CT 06520 USA
[2] Univ S Florida, H Lee Moffitt Canc Ctr, Drug Discovery Program, Tampa, FL 33612 USA
[3] Univ S Florida, Res Inst, Dept Oncol, Tampa, FL 33612 USA
[4] Univ S Florida, Dept Biochem & Mol Biol, Tampa, FL 33612 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2005年 / 13卷 / 03期
关键词：
geranylgeranyltransferase-I; peptidomimetics; farnesyltransferase; antitumor agents;
D O I：
10.1016/j.bmc.2004.10.053
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
A series of novel protein geranylgeranyltransferase-I (PGGTase-I) inhibitors based on a benzoyleneurea scaffold has been synthesized. Using a benzoyleneurea scaffold as a mimetic for the central dipeptide (AA), we have developed CAAX peptidomimetic inhibitors that selectively block the activity of PGGTase-I over the closely related enzyme protein farnesyltransferase. In this new class of PGGTase-I inhibitors, compound (6c) with X = L-phenylalanine displayed the highest inhibition activity against PGGTase-I with an IC50 value of 170 nM. The inhibitors described in this study represent novel and promising leads for the development of potent and selective inhibitors of mammalian PGGTase-I for potential application as antitumor agents. (C) 2004 Elsevier Ltd. All rights reserved.
引用
收藏
页码：677 / 688
页数：12
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