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Identification of para ‐Substituted Benzoic Acid Derivatives as Potent Inhibitors of the Protein Phosphatase Slingshot
Author(s) -
Li Kangshuai,
Xiao Peng,
Zhang Daolai,
Hou XuBen,
Ge Lin,
Yang Duxiao,
Liu Hongda,
He Dongfang,
Chen Xu,
Han Kerui,
Song Xiaoyuan,
Yu Xiao,
Fang Hao,
Sun Jinpeng
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500454
Subject(s) - dephosphorylation , chemistry , phosphatase , benzoic acid , cofilin , biochemistry , kinase , phosphorylation , cell , cytoskeleton , actin cytoskeleton
Slingshot proteins form a small group of dual‐specific phosphatases that modulate cytoskeleton dynamics through dephosphorylation of cofilin and Lim kinases (LIMK). Small chemical compounds with Slingshot‐inhibiting activities have therapeutic potential against cancers or infectious diseases. However, only a few Slingshot inhibitors have been investigated and reported, and their cellular activities have not been examined. In this study, we identified two rhodanine‐scaffold‐based para ‐substituted benzoic acid derivatives as competitive Slingshot inhibitors. The top compound, ( Z )‐4‐((4‐((4‐oxo‐2‐thioxo‐3‐( o ‐tolyl)thiazolidin‐5‐ylidene)methyl)phenoxy)methyl)benzoic acid ( D3 ) had an inhibition constant ( K i ) of around 4 μ m and displayed selectivity over a panel of other phosphatases. Moreover, compound D3 inhibited cell migration and cofilin dephosphorylation after nerve growth factor (NGF) or angiotensin II stimulation. Therefore, our newly identified Slingshot inhibitors provide a starting point for developing Slingshot‐targeted therapies.