title: Identification of para-Substituted Benzoic Acid Derivatives as Potent Inhibitors of the Protein Phosphatase Slingshot.
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.
authors.affiliation: 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.|Department of Physiology, School of Medicine, Shandong University, Jinan, Shandong, 250012, China.
authors.forename: Kang-shuai
authors.initials: KS
authors.lastname: Li
authors.affiliation: 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.|Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong, 250012, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xiao
authors.affiliation: 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.|School of Pharmacy, Binzhou Medical University, Yantai, 264003, China.
authors.forename: Dao-lai
authors.initials: DL
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong, 250012, China.
authors.forename: Xu-Ben
authors.initials: XB
authors.lastname: Hou
authors.affiliation: 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.
authors.forename: Lin
authors.initials: L
authors.lastname: Ge
authors.affiliation: 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.
authors.forename: Du-xiao
authors.initials: DX
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Hong-da
authors.initials: HD
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Dong-fang
authors.initials: DF
authors.lastname: He
authors.affiliation: Department of Physiology, School of Medicine, Shandong University, Jinan, Shandong, 250012, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Mailman School of Public Health, Columbia University, New York, NY, 10032, USA.
authors.forename: Ke-rui
authors.initials: KR
authors.lastname: Han
authors.affiliation: 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.
authors.forename: Xiao-yuan
authors.initials: XY
authors.lastname: Song
authors.affiliation: Department of Physiology, School of Medicine, Shandong University, Jinan, Shandong, 250012, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Hao
authors.initials: H
authors.lastname: Fang
authors.affiliation: 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. sunjinpeng@sdu.edu.cn.
authors.forename: Jin-peng
authors.initials: JP
authors.lastname: Sun
mesh_terms: D000818:Animals; D001565:Benzoates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D019817:Benzoic Acid / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D054461:Lim Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D016716:PC12 Cells; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C000611537:4-((4-((4-oxo-2-thioxo-3-(o-tolyl)thiazolidin-5-ylidene)methyl)phenoxy)methyl)benzoic acid; D001565:Benzoates; D004791:Enzyme Inhibitors; D012236:Rhodanine; D019817:Benzoic Acid; D020932:Nerve Growth Factor; D054461:Lim Kinases; D010749:Phosphoprotein Phosphatases
keywords: Slingshot; anticancer; cell migration; nerve growth factor (NGF); phosphatase inhibitors