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Structure-Activity Relationship of NF023 Derivatives Binding to XIAP-BIR1

Luca Sorrentino1, Federica Cossu1, Mario Milani1,2

  • 1CNR-IBF Via Celoria 26 I-20133 Milano Italy.

Chemistryopen
|April 24, 2019
PubMed

Insights

Inhibitors of Apoptosis Proteins (IAPs) regulate cell survival pathways often altered in cancer. This study shows NF023 inhibits XIAP-BIR1 dimerization, offering a potential strategy against cancer cell survival.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Structural Biology

Background:

  • Inhibitors of Apoptosis Proteins (IAPs) are E3-ligases crucial for preventing apoptosis and activating NF-kB survival pathways, frequently dysregulated in cancer.
  • IAP-mediated NF-kB signaling relies on type-I BIR domain protein complex formation, where XIAP-BIR1 dimerization binds TAB1 monomers, promoting NF-kB activation.
  • Inhibiting XIAP-BIR1 dimerization presents a novel therapeutic strategy to impede cancer cell survival.

Purpose of the Study:

  • To thoroughly analyze the binding of NF023 to the XIAP-BIR1 domain.
  • To investigate the molecular mechanisms underlying NF023's interaction with XIAP-BIR1.
  • To provide insights for developing novel BIR1-specific pro-apoptotic agents.

Main Methods:

  • Biochemical assays to assess protein interactions.
  • Biophysical techniques to characterize binding kinetics and thermodynamics.
  • X-ray crystallography or Cryo-EM to determine the structural basis of NF023-XIAP-BIR1 interaction.

Main Results:

  • NF023 directly binds to the XIAP-BIR1 domain.
  • The dimerization interface of XIAP-BIR1 is implicated in NF023 binding.
  • NF023's overall symmetry and central chemical features are critical for effective binding.

Conclusions:

  • NF023 effectively inhibits XIAP-BIR1 dimerization.
  • The findings highlight the XIAP-BIR1 dimerization interface as a target for drug development.
  • This research offers a promising avenue for creating novel pro-apoptotic compounds for cancer therapy.
Keywords:
apoptosisdrug discoveryin silico dockingprotein structuresstructure-activity relationship

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