Structure-based design, synthesis, evaluation, and crystallographic studies of conformationally constrained Smac mimetics as inhibitors of the X-linked inhibitor of apoptosis protein (XIAP)

J Med Chem. 2008 Nov 27;51(22):7169-80. doi: 10.1021/jm8006849.

Abstract

Small molecules designed to mimic the binding of Smac protein to X-linked inhibitor of apoptosis protein (XIAP) are being pursued as a promising new class of anticancer drugs. Herein, we report the design, synthesis, and comprehensive structure-activity relationship studies of a series of conformationally constrained bicyclic Smac mimetics. Our studies led to the discovery of a number of highly potent and cell-permeable Smac mimetics and yielded important new insights into their structure-activity relationship for their binding to XIAP and for their activity in inhibition of cancer cell growth. Determination of the crystal structure of one potent Smac mimetic, compound 21, in complex with XIAP BIR3 provides the structural basis for its high-affinity binding to XIAP and for the design of highly potent Smac mimetics.

Publication types

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

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis Regulatory Proteins
  • Binding Sites
  • Cell Line, Tumor
  • Cell Membrane Permeability / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mitochondrial Proteins / chemistry*
  • Mitochondrial Proteins / metabolism
  • Models, Molecular
  • Molecular Conformation
  • Molecular Mimicry*
  • Molecular Weight
  • Structure-Activity Relationship
  • Time Factors
  • X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors*
  • X-Linked Inhibitor of Apoptosis Protein / chemistry
  • X-Linked Inhibitor of Apoptosis Protein / metabolism

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • DIABLO protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • X-Linked Inhibitor of Apoptosis Protein