Identification of para-Substituted Benzoic Acid Derivatives as Potent Inhibitors of the Protein Phosphatase Slingshot

  • ChemMedChem. 2015 Dec;10(12):1980-7. doi: 10.1002/cmdc.201500454.
Kang-shuai Li  1  2 ,  Peng Xiao  1  3 ,  Dao-lai Zhang  1  4 ,  Xu-Ben Hou  3 ,  Lin Ge  1 ,  Du-xiao Yang  1 ,  Hong-da Liu  1 ,  Dong-fang He  1 ,  Xu Chen  2 ,  Ke-rui Han  5 ,  Xiao-yuan Song  6 ,  Xiao Yu  2 ,  Hao Fang  1 ,  Jin-peng Sun  7
Affiliations
  • 1. Key Laboratory Experimental Teratology of the Ministry of Education (MOE) and, Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 2. Department of Physiology, School of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 3. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong, 250012, China.
  • 4. School of Pharmacy, Binzhou Medical University, Yantai, 264003, China.
  • 5. Mailman School of Public Health, Columbia University, New York, NY, 10032, USA.
  • 6. Key Laboratory of Brain Function and Disease, Chinese Academy of Sciences (CAS) and, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, China.
  • 7. Key Laboratory Experimental Teratology of the Ministry of Education (MOE) and, Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, Shandong, 250012, China. [email protected].
PMID: 26553423 DOI: 10.1002/cmdc.201500454
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 (Ki) of around 4 μm 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.

Keywords
Slingshot; anticancer; cell migration; nerve growth factor (NGF); phosphatase inhibitors.
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