BH3 mimetics derived from Bim-BH3 domain core region show PTP1B inhibitory activity

Bioorg Med Chem Lett. 2019 Jan 15;29(2):244-247. doi: 10.1016/j.bmcl.2018.11.047. Epub 2018 Nov 23.

Abstract

A series of our previously described BH3 peptide mimetics derived from Bim-BH3 domain core region were found to exhibit weak to potent PTP1B binding affinity and inhibitory activities via target-based drug screening. Among these compounds, a 12-aa Bim-BH3 core sequence peptide conjugated to palmitic acid (SM-6) displayed good PTP1B binding affinity (KD = 8.38 nmol/L), inhibitory activity (IC50 = 1.20 μmol/L) and selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). Furthermore, SM-6 promoted HepG2 cell glucose uptake and inhibited the expression of PTP1B, indicating that SM-6 could improve the insulin resistance effect in the insulin-resistant HepG2 cell model. These results may indicate a new direction for the application of BH3 peptide mimetics and promising PTP1B peptide inhibitors could be designed and developed based on SM-6.

Keywords: BH3 peptide mimetics; Insulin resistance; PTP1B inhibitors; Protein tyrosine phosphatase 1B; Type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Hep G2 Cells
  • Humans
  • Molecular Structure
  • Palmitic Acid / chemistry
  • Palmitic Acid / pharmacology*
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Structure-Activity Relationship

Substances

  • Peptides
  • Palmitic Acid
  • PTPN1 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1