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Identification of small-molecule inhibitors of USP2a

Marcin D Tomala1, Katarzyna Magiera-Mularz1, Katarzyna Kubica1

  • 1Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387, Krakow, Poland.

European Journal of Medicinal Chemistry
|March 13, 2018
PubMed

Insights

Researchers discovered novel small molecules that inhibit USP2a, a protein linked to cancer growth by stabilizing cyclin D1. This finding offers a promising new strategy for developing cancer therapies targeting USP2a.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Ubiquitin-specific protease 2a (USP2a) deubiquitinating enzyme promotes cancer by stabilizing oncogenic proteins like cyclin D1.
  • Targeting USP2a is a potential cancer therapy strategy, but effective inhibitors are lacking.

Purpose of the Study:

  • To discover and develop novel small molecule inhibitors of USP2a.
  • To identify a new pharmacophore for USP2a-targeted cancer therapeutics.

Main Methods:

  • Utilized NMR-based fragment screening to identify USP2a binders.
  • Employed biophysical binding assays to characterize inhibitor interactions.
  • Applied structure-driven design and fragment combination for optimization.

Main Results:

  • Identified two 5-(2-thienyl)-3-isoxazole compounds as inhibitors of USP2a.
  • Demonstrated that these inhibitors block the USP2a-ubiquitin protein-protein interaction.
  • Confirmed that inhibitor affinity correlates with functional inhibition of USP2a.

Conclusions:

  • The 5-(2-thienyl)-3-isoxazole scaffold is a promising starting point for developing USP2a inhibitors.
  • These findings provide a foundation for optimizing lead compounds for cancer therapy.
  • This study advances the development of novel strategies to target USP2a in cancer treatment.
Keywords:
AnticancerDeubiquitinaseHeterocyclicsSmall-molecular inhibitorsUbiquitin

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