Novel PTP1B inhibitors identified by DNA display of fragment pairs

Bioorg Med Chem Lett. 2016 Feb 1;26(3):1080-1085. doi: 10.1016/j.bmcl.2015.11.102. Epub 2015 Nov 28.

Abstract

DNA display of PNA-encoded libraries was used to pair fragments containing different phosphotyrosine surrogates with diverse triazoles. Microarray-based screening of the combinatorially paired fragment sets (62,500 combinations) against a prototypical phosphatase, PTP1B, was used to identify the fittest fragments. A focused library (10,000 members) covalently pairing identified fragments with linkers of different length and geometry was synthesized. Screening of the focused library against PTP1B and closely related TCPTP revealed orthogonal inhibitors. The selectivity of the identified inhibitors for PTP1B versus TCPT was confirmed by enzymatic inhibition assay.

Keywords: DNA-encoded library; Fragment based drug discovery; PTP1B; Peptide nucleic acid (PNA).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA / chemistry
  • DNA / metabolism*
  • Enzyme Inhibitors / chemistry*
  • Humans
  • Microarray Analysis
  • Peptide Nucleic Acids / chemistry
  • Protein Binding
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism

Substances

  • Enzyme Inhibitors
  • Peptide Nucleic Acids
  • Small Molecule Libraries
  • DNA
  • PTPN1 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1