Peptidyl prolyl isomerase Pin1-inhibitory activity of D-glutamic and D-aspartic acid derivatives bearing a cyclic aliphatic amine moiety

被引：9

作者：

Nakagawa, Hidehiko ^{[1
]}

Seike, Suguru ^{[1
]}

Sugimoto, Masatoshi ^{[1
]}

Ieda, Naoya ^{[1
]}

Kawaguchi, Mitsuyasu ^{[1
]}

Suzuki, Takayoshi ^{[2
]}

Miyata, Naoki ^{[1
]}

机构：

[1] Nagoya City Univ, Grad Sch Pharmaceut Sci, Mizuho Ku, Nagoya, Aichi 4678603, Japan

[2] Kyoto Prefectural Univ Med, Grad Sch Med Sci, Kyoto, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 23期

关键词：

cis-trans isomerization; Proline; Phosphoserine; Phosphothreonine; PIN1; INHIBITORS; STRUCTURAL BASIS; DRUG DISCOVERY; BREAST-CANCER; PHOSPHORYLATION; ISOMERIZATION; TARGET;

D O I：

10.1016/j.bmcl.2015.10.033

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Pin1 is a peptidyl prolyl isomerase that specifically catalyzes cis-trans isomerization of phosphorylated Thr/Ser-Pro peptide bonds in substrate proteins and peptides. Pin1 is involved in many important cellular processes, including cancer progression, so it is a potential target of cancer therapy. We designed and synthesized a novel series of Pin1 inhibitors based on a glutamic acid or aspartic acid scaffold bearing an aromatic moiety to provide a hydrophobic surface and a cyclic aliphatic amine moiety with affinity for the proline-binding site of Pin1. Glutamic acid derivatives bearing cycloalkylamino and phenylthiazole groups showed potent Pin1-inhibitory activity comparable with that of known inhibitor VER-1. The results indicate that steric interaction of the cyclic alkyl amine moiety with binding site residues plays a key role in enhancing Pin1-inhibitory activity. (C) 2015 The Authors. Published by Elsevier Ltd.

引用

页码：5619 / 5624

页数：6