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Published on: October 28, 2014

Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity

Aaron D Schimmer1, Kate Welsh, Clemencia Pinilla

  • 1The Burnham Institute, La Jolla, CA 92037, USA.

Cancer Cell
|January 30, 2004
PubMed

Insights

Researchers identified polyphenylureas that inhibit XIAP, a protein overexpressed in cancers that blocks cell death. These compounds promote cancer cell death and reduce tumor growth, validating IAPs as drug targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Cancer cells often resist apoptosis, a key cell death pathway.
  • X-linked inhibitor of apoptosis protein (XIAP) is an endogenous caspase inhibitor overexpressed in many cancers, contributing to apoptosis resistance.

Purpose of the Study:

  • To identify novel compounds that overcome XIAP-mediated caspase inhibition.
  • To validate Inhibitor of Apoptosis Proteins (IAPs) as therapeutic targets for cancer treatment.

Main Methods:

  • Development of an enzyme derepression assay to screen for XIAP inhibitors.
  • Screening of mixture-based combinatorial chemical libraries.
  • In vitro testing of compound efficacy on cancer cell lines and in vivo xenograft models.

Main Results:

  • Identification of a class of polyphenylureas with XIAP-inhibitory activity.
  • Active compounds increased caspase activity, induced apoptosis in tumor cell lines, and sensitized cells to chemotherapy.
  • Compounds suppressed tumor growth in mouse xenograft models with minimal toxicity to normal tissues.

Conclusions:

  • Polyphenylureas effectively inhibit XIAP and promote cancer cell death.
  • IAPs represent a promising target class for the development of novel cancer therapeutics.

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