Novel, potent, selective and cellular active ABC type PTP1B inhibitors containing (methanesulfonyl-phenyl-amino)-acetic acid methyl ester phosphotyrosine mimetic

Peihong Liu; Yongli Du; Lianhua Song; Jingkang Shen; Qunyi Li

doi:10.1016/j.bmc.2015.09.024

Novel, potent, selective and cellular active ABC type PTP1B inhibitors containing (methanesulfonyl-phenyl-amino)-acetic acid methyl ester phosphotyrosine mimetic

Bioorg Med Chem. 2015 Nov 1;23(21):7079-88. doi: 10.1016/j.bmc.2015.09.024. Epub 2015 Sep 15.

Authors

Peihong Liu¹, Yongli Du², Lianhua Song¹, Jingkang Shen³, Qunyi Li⁴

Affiliations

¹ School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, 3501 Daxue Road, Jinan 250353, China.
² School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, 3501 Daxue Road, Jinan 250353, China. Electronic address: ylduyjs@163.com.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
⁴ Clinical Pharmacy Laboratory, Huashan Hospital, Fudan University, 12 Wu Lu Mu Qi M Road, Shanghai 200040, China. Electronic address: qyli1234@163.com.

PMID: 26481657
DOI: 10.1016/j.bmc.2015.09.024

Abstract

Protein tyrosine phosphatase 1B (PTP1B) which plays an important role in the negative regulation of insulin and leptin pathway has emerged as a novel promising therapeutic target for the treatment of type 2 diabetes mellitus and obesity. Upon careful study, a series of novel scaffold and simple synthesis method inhibitors were discovered based on the analysis of X-ray crystal structures of PTP1B/inhibitor complexes and docking simulations. Among them, compound P7 exhibited high inhibitory activity (IC50=222 nM) with moderate selectivity (8-fold) over T-cell PTPase (TCPTP) through interacting with the A, B and C binding sites of PTP1B enzyme. Further studies on cellular activities revealed that compound P7 could enhance insulin-mediated IRβ phosphorylation and insulin-stimulated glucose uptake.

Keywords: Inhibitor; PTP1B; Structure–activity relationships; Type 2 diabetes mellitus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites
Biocompatible Materials / chemical synthesis
Biocompatible Materials / chemistry*
Biocompatible Materials / metabolism
CHO Cells
Cell Line
Cricetinae
Cricetulus
Crystallography, X-Ray
Drug Design
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Glucose / metabolism
Inhibitory Concentration 50
Insulin / pharmacology
Mice
Molecular Docking Simulation
Phosphorylation
Phosphotyrosine / chemistry*
Protein Structure, Tertiary
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
Receptor, Insulin / metabolism
Structure-Activity Relationship

Substances

Biocompatible Materials
Enzyme Inhibitors
Insulin
Phosphotyrosine
Receptor, Insulin
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Glucose