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A new "angle" on kinase inhibitor design: Prioritizing amphosteric activity above kinase inhibition

Justin G Meyerowitz1, William A Weiss2, W Clay Gustafson3

  • 1Department of Cellular and Molecular Pharmacology; School of Medicine; Helen Diller Family Comprehensive Cancer Center.

Molecular & Cellular Oncology
|June 17, 2016
PubMed

Insights

Scientists developed novel kinase inhibitors to target the MYCN oncoprotein by disrupting Aurora kinase A. This approach leads to MYCN degradation, offering a new strategy for targeting enzyme activity-independent functions.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The MYCN oncoprotein is a challenging therapeutic target in various cancers.
  • Kinases play crucial roles in cellular processes, and their dysregulation is linked to disease.

Purpose of the Study:

  • To develop a novel therapeutic strategy targeting the MYCN oncoprotein.
  • To investigate a new class of kinase inhibitors designed to disrupt Aurora kinase A's interaction with MYCN.

Main Methods:

  • Design and synthesis of novel kinase inhibitors.
  • Biochemical assays to assess Aurora kinase A conformation and MYCN interaction.
  • Cellular studies to evaluate MYCN degradation and downstream effects.

Main Results:

  • A new class of kinase inhibitors effectively disrupts Aurora kinase A conformation.
  • Inhibitors block the kinase-independent interaction between Aurora kinase A and MYCN.
  • This blockade results in potent degradation of the MYCN oncoprotein.

Conclusions:

  • The study demonstrates a proof-of-principle for targeting enzyme activity-independent functions.
  • This approach offers a novel method for targeting elusive oncoproteins like MYCN.
  • The findings open new avenues for cancer therapy development.
Keywords:
AURKAAurora kinase AMYCMYCNcancerkinase inhibition

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