Design, synthesis and evaluation of monovalent Smac mimetics that bind to the BIR2 domain of the anti-apoptotic protein XIAP

Bioorg Med Chem Lett. 2011 Jul 15;21(14):4332-6. doi: 10.1016/j.bmcl.2011.05.049. Epub 2011 May 24.

Abstract

We report the systematic rational design and synthesis of new monovalent Smac mimetics that bind preferentially to the BIR2 domain of the anti-apoptotic protein XIAP. Characterization of compounds in vitro (including 9i; ML101) led to the determination of key structural requirements for BIR2 binding affinity. Compounds 9h and 9j sensitized TRAIL-resistant breast cancer cells to apoptotic cell death, highlighting the value of these probe compounds as tools to investigate the biology of XIAP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Apoptosis Regulatory Proteins / chemistry*
  • Binding Sites
  • Biomimetic Materials / chemical synthesis
  • Biomimetic Materials / chemistry
  • Biomimetic Materials / pharmacology
  • Cell Line, Tumor
  • Computer Simulation
  • Drug Design
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mitochondrial Proteins / chemistry*
  • Mitochondrial Proteins / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors*
  • X-Linked Inhibitor of Apoptosis Protein / chemistry
  • X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • DIABLO protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • X-Linked Inhibitor of Apoptosis Protein