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Kinases Controlling Stability of the Oncogenic MYCN Protein

Nailah Smith1, Eduard Reznik1, Brygida Bisikirska2

  • 1Department of Biological Sciences, Columbia University, New York City, New York 10027, United States.

ACS Medicinal Chemistry Letters
|December 20, 2023
PubMed

Insights

Natural products isopomiferin and pomiferin indirectly degrade MYCN by targeting key kinases like CK2 and PI3K. This approach offers a novel strategy for targeting MYCN in neuroblastoma cells.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • MYCN is a key oncogene in neuroblastoma (NBL) and is considered
  • undruggable
  • due to its lack of canonical binding sites.

Purpose of the Study:

  • To elucidate the mechanism of action of isopomiferin and pomiferin in MYCN ablation.
  • To identify key kinases involved in maintaining MYCN stability.
  • To develop novel, cost-effective pomiferin analogues for MYCN targeting.

Main Methods:

  • Systematic inhibition of identified kinases (CK2, PI3K, CHK1, STK38L, STK38).
  • Synthesis and testing of pomiferin analogues.
  • Assessment of MYCN degradation and NBL cell death induction.

Main Results:

  • Identified a kinase network (CK2, PI3K, CHK1, STK38L, STK38) maintaining MYCN stability.
  • Inhibition of these kinases led to MYCN degradation and NBL cell death.
  • Synthesized pomiferin analogues retained MYCN ablating activity.

Conclusions:

  • Established a novel indirect targeting strategy for MYCN in NBL cells.
  • Demonstrated the therapeutic potential of targeting the identified kinase network.
  • Pomiferin analogues represent promising, cost-effective therapeutic leads.

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