Isolation of a small-molecule inhibitor of the antiapoptotic protein Bcl-xL from a DNA-encoded chemical library

ChemMedChem. 2010 Apr 6;5(4):584-90. doi: 10.1002/cmdc.200900520.

Abstract

Bcl-xL is an antiapoptotic member of the Bcl-2 protein family and an attractive target for the development of anticancer agents. Here we describe the isolation of binders to Bcl-xL from a DNA-encoded chemical library using affinity-capture selections and massively parallel high-throughput sequencing of >30,000 sequence tags of library members. The most potent binder identified, compound 19/93 [(R)-3-(amido indomethacin)-4-(naphthalen-1-yl)butanoic acid], bound to Bcl-xL with a dissociation constant (K(d)) of 930 nM and was able to compete with a Bak-derived BH3 peptide, an antagonist of Bcl-xL function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / toxicity
  • Apoptosis
  • Cell Line, Tumor
  • DNA / chemistry*
  • Humans
  • Sequence Analysis, DNA
  • Small Molecule Libraries
  • bcl-X Protein / antagonists & inhibitors*
  • bcl-X Protein / metabolism

Substances

  • Antineoplastic Agents
  • Small Molecule Libraries
  • bcl-X Protein
  • DNA