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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Nakagawa, Hidehiko¹  Seike, Suguru¹  Sugimoto, Masatoshi¹  Ieda, Naoya¹  Kawaguchi, Mitsuyasu¹  Suzuki, Takayoshi²  Miyata, Naoki¹ 

[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

关键词: cis-trans isomerization;    Proline;    Phosphoserine;    Phosphothreonine;   

DOI  :  10.1016/j.bmcl.2015.10.033

来源: Elsevier

【 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.

【 授权许可】

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