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Boron-based inhibitors of acyl protein thioesterases 1 and 2

Tobias J Zimmermann1, Marco Bürger, Etsu Tashiro

  • 1Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.

Chembiochem : a European Journal of Chemical Biology
|December 15, 2012
PubMed

Insights

New boronic and borinic acid derivatives show potent, non-toxic inhibition of acyl protein thioesterases (APT1 and APT2), key targets in cancer therapy. These compounds modulate the Ras cycle and inhibit Erk1/2 phosphorylation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Ras proteins are crucial for cell proliferation, and their mutations are implicated in various cancers.
  • The Ras cycle is a key regulator of cell growth, and its modulation is a therapeutic strategy.
  • Acyl protein thioesterases (APT1 and APT2) are enzymes involved in the Ras cycle, making them potential drug targets.

Purpose of the Study:

  • To identify and characterize novel inhibitors of APT1 and APT2.
  • To explore the potential of boronic and borinic acid derivatives as therapeutic agents for cancer.
  • To investigate the effect of these inhibitors on the Ras pathway and downstream signaling.

Main Methods:

  • Extensive library screening using chemical arrays to identify APT inhibitors.
  • In vitro assays to determine the inhibitory activity and mode of action against human APT1 and APT2.
  • Biochemical assays to assess the impact of inhibitors on Erk1/2 phosphorylation.

Main Results:

  • Discovery of a new class of potent and non-toxic boronic and borinic acid derivatives as APT inhibitors.
  • Demonstration of competitive inhibition of human APT1 and APT2 by these compounds.
  • Significant inhibition of Erk1/2 phosphorylation by a lead molecule, indicating pathway modulation.

Conclusions:

  • Boronic and borinic acid derivatives represent a promising new class of APT inhibitors.
  • These inhibitors offer a novel approach to targeting the Ras cycle for cancer therapy.
  • The identified compounds have the potential to modulate key signaling pathways involved in cancer progression.

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