Relaxation of the rigid backbone of an oligoamide-foldamer-based α-helix mimetic: identification of potent Bcl-xL inhibitors

Org Biomol Chem. 2012 Apr 21;10(15):2928-33. doi: 10.1039/c2ob07125h. Epub 2012 Mar 7.

Abstract

By conducting a structure-activity relationship study of the backbone of a series of oligoamide-foldamer-based α-helix mimetics of the Bak BH3 helix, we have identified especially potent inhibitors of Bcl-x(L). The most potent compound has a K(i) value of 94 nM in vitro, and single-digit micromolar IC(50) values against the proliferation of several Bcl-x(L)-overexpressing cancer cell lines.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amides / chemical synthesis
  • Amides / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Benzamides / chemical synthesis*
  • Benzamides / pharmacology
  • Binding Sites
  • Biomimetic Materials / chemical synthesis*
  • Biomimetic Materials / pharmacology
  • Cell Line, Tumor
  • Humans
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Peptide Fragments / chemistry
  • Picolinic Acids / chemical synthesis*
  • Picolinic Acids / pharmacology
  • Protein Binding
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Thermodynamics
  • bcl-2 Homologous Antagonist-Killer Protein / chemistry
  • bcl-X Protein / antagonists & inhibitors*
  • bcl-X Protein / chemistry

Substances

  • Amides
  • Antineoplastic Agents
  • Benzamides
  • Peptide Fragments
  • Picolinic Acids
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-X Protein
  • picolinamide