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Small-Molecule Inhibitors of the Tumor Suppressor Fhit

Sandra Lange1, Stephan M Hacker1,2, Philipp Schmid1

  • 1Department of Chemistry, Konstanz Research School-Chemical Biology, University of Konstanz, Universitätsstrasse 10, 78457, Konstanz, Germany.

Chembiochem : a European Journal of Chemical Biology
|June 24, 2017
PubMed

Insights

Researchers developed a high-throughput screen to find small-molecule inhibitors of the tumor suppressor Fhit. This screen identified potent inhibitors crucial for studying Fhit

Area of Science:

  • Oncology
  • Biochemistry
  • Molecular Biology

Background:

  • The tumor suppressor Fhit and its substrate diadenosine triphosphate (Ap3A) play critical roles in cancer development and progression.
  • Fhit possesses Ap3A hydrolase activity, cleaving Ap3A into AMP and ADP, which is thought to terminate Fhit-mediated signaling.
  • Mechanisms regulating Fhit's catalytic activity and its growth-suppressive functions remain largely unknown.

Purpose of the Study:

  • To develop a high-throughput screening method for identifying small-molecule inhibitors of Fhit enzymatic activity.
  • To provide valuable tools for investigating the tumor-suppressive functions of Fhit.

Main Methods:

  • Development and implementation of a high-throughput screen (HTS) assay.
  • Identification of inhibitor compounds targeting Fhit activity.
  • Synthesis and in vitro characterization of selected inhibitor derivatives.

Main Results:

  • Two distinct clusters of small-molecule inhibitors significantly reduced Fhit activity by over 90%.
  • Synthesized derivatives demonstrated potent in vitro inhibitory activity with IC50 values in the nanomolar range.

Conclusions:

  • The developed HTS assay successfully identified potent inhibitors of Fhit enzymatic activity.
  • These novel inhibitors serve as valuable chemical probes for further research into Fhit's role in cancer.
Keywords:
Ap3AFRETFhitenzyme inhibitorsnucleotides

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