title: Discovery of Bisindole as a Novel Scaffold for Protein Tyrosine Phosphatase 1B Inhibitors.
abstract: Protein tyrosine phosphatase 1B (PTP1B) has been proposed to be an effective target for the treatment of both type II diabetes and obesity. However, no PTP1B inhibitor has come into clinic application. Herein, we report mixed 3,3'-bisindoles as novel PTP1B inhibitors with low micromole-ranged inhibitory activity. The best active compound 9f inhibited PTP1B activity with an IC50of 2.79 µM. Meanwhile, it had low cytotoxicity and enhanced glucose uptake in vitro. Further studies demonstrated that some of these active compounds had a specific selectivity over other PTPs. Computational analysis further showed the binding mode of compound 9f with the active pocket of PTP1B. Our studies provide a novel scaffold for further development of more promising PTP1B inhibitors and potential drugs for type II diabetes and obesity.
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Changcheng
authors.initials: C
authors.lastname: Jing
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Ziyan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Kaili
authors.initials: K
authors.lastname: Jia
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Liu
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Wang
authors.forename: Wenhao
authors.initials: W
authors.lastname: Hu
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
authors.forename: Suzhen
authors.initials: S
authors.lastname: Dong
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D005947:Glucose
keywords: Inhibitor; Mixed 3,3′-bisindoles; Molecular docking; Protein tyrosine phosphatase 1B