Identification of para‐Substituted Benzoic Acid Derivatives as Potent Inhibitors of the Protein Phosphatase Slingshot. Issue 12 (10th November 2015)

• Record Type: Journal Article
• Authors: Li, Kang‐shuai; Xiao, Peng; Zhang, Dao‐lai; Hou, Xu‐Ben; Ge, Lin; Yang, Du‐xiao; Liu, Hong‐da; He, Dong‐fang; Chen, Xu; Han, Ke‐rui; Song, Xiao‐yuan; Yu, Xiao; Fang, Hao; Sun, Jin‐peng
• Is Part Of: ChemMedChem. Volume 10:Issue 12(2015:Dec.)
• Page Start: 1980
• Page End: 1987
• Publication Date: 2015-11-10
• Subjects: anticancer -- cell migration -- nerve growth factor (NGF) -- phosphatase inhibitors -- Slingshot; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500454
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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 μm and displayed selectivity over a panel of other phosphatases. Moreover, compoundD3 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. Abstract : Battling cancer by Slingshot ! Small compounds with Slingshot‐inhibiting activity have therapeutic potential against cancers or infectious diseases. Compounds containing a benzoic acid group were selected and screened for inhibition of Slingshot 2 phosphatase activity. Two rhodanine‐scaffold‐based para ‐substituted benzoic acid derivatives were competitive inhibitors and now provide a starting point for developing Slingshot‐targeted therapies.