Structure-based design of potent, conformationally constrained Smac mimetics

J Am Chem Soc. 2004 Dec 29;126(51):16686-7. doi: 10.1021/ja047438+.

Abstract

A successful structure-based design and synthesis of a class of highly potent conformationally constrained Smac mimetics is described. The most potent compound has a Ki value of 25 nM binding to the XIAP BIR3 protein and is 23 times more potent than natural Smac peptides. These potent Smac mimetics can serve as powerful chemical and pharmacological tools to further elucidate the role of Smac and its cellular binding partners in apoptosis regulation and may be developed as a new class of anti-cancer drugs.

Publication types

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

MeSH terms

  • Apoptosis Regulatory Proteins
  • Binding, Competitive
  • Biomimetic Materials / chemistry*
  • Biomimetic Materials / metabolism*
  • Carrier Proteins / chemistry*
  • Carrier Proteins / metabolism*
  • Drug Design*
  • Etoposide / pharmacology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Jurkat Cells
  • Mitochondrial Proteins / chemistry*
  • Mitochondrial Proteins / metabolism*
  • Protein Conformation
  • Proteins / chemistry
  • Proteins / metabolism
  • Structure-Activity Relationship
  • X-Linked Inhibitor of Apoptosis Protein

Substances

  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • DIABLO protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Proteins
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Etoposide