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2-Phenylquinazolinones as dual-activity tankyrase-kinase inhibitors

Yves Nkizinkiko1, Jenny Desantis2, Jarkko Koivunen1

  • 1Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland.

Scientific Reports
|January 28, 2018
PubMed

Insights

This study reveals that 2-phenylquinazolinones (2-PQs) are potent tankyrase (TNKS) inhibitors, offering a new avenue for anti-cancer drug development targeting the Wnt/β-catenin pathway.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Oncology

Background:

  • Tankyrases (TNKSs) are key regulators of the Wnt/β-catenin pathway and validated anti-cancer drug targets.
  • Developing potent and selective TNKS inhibitors is crucial for advancing cancer therapeutics.

Purpose of the Study:

  • To profile 2-phenylquinazolinones (2-PQs) as potential tankyrase inhibitors.
  • To investigate the selectivity of 2-PQs against tankyrases versus other kinases, particularly CDK9 and Akt.
  • To elucidate the structural basis for selectivity between tankyrases and kinases.

Main Methods:

  • Profiling of 2-PQs against TNKS and Wnt/β-catenin pathway kinases.
  • Evaluation of compound selectivity against the ARTD enzyme family.
  • Co-crystal structure determination of TNKS2-inhibitor complexes.
  • Comparative structure-based analysis and molecular docking studies.

Main Results:

  • 2-Phenylquinazolinones (2-PQs) demonstrated significantly higher potency as TNKS inhibitors compared to CDK9 inhibitors.
  • Compounds exhibited selectivity for tankyrases over other ARTD family members.
  • Structural studies revealed key features governing selectivity for TNKS over kinases like CDK9 and Akt.
  • A single compound was identified with equal micromolar potency against TNKS, CDK9, and Akt.

Conclusions:

  • 2-Phenylquinazolinones represent a promising class of compounds for targeting tankyrases in cancer therapy.
  • Understanding the structural basis of selectivity can guide the design of more effective and specific anti-cancer agents.
  • The identified multi-kinase inhibitor warrants further investigation for its therapeutic potential.

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