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Inhibitors of the Oncogenic PA2G4-MYCN Protein-Protein Interface

Hassina Massudi1, Jie-Si Luo1,2, Jessica K Holien3,4

  • 1Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2750, Australia.

Cancers
|March 29, 2023
PubMed

Insights

New WS6 analogues target the PA2G4-MYCN interaction, inhibiting neuroblastoma growth with reduced toxicity. This discovery offers a potential first-in-class therapy for MYCN-driven cancers.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • MYCN is a key driver of neuroblastoma, but direct inhibitors are lacking.
  • PA2G4 is a MYCN-binding partner crucial for neuroblastoma tumorigenesis.
  • WS6, a PA2G4 binder, reduced neuroblastoma growth in mice by inhibiting PA2G4-MYCN interaction.

Purpose of the Study:

  • To identify and characterize novel WS6 analogues with improved efficacy and reduced toxicity.
  • To investigate the structure-activity relationships of WS6 analogues targeting PA2G4.
  • To evaluate the therapeutic potential of WS6 analogues in neuroblastoma models.

Main Methods:

  • Synthesis and structural analysis of WS6 analogues.
  • Surface plasmon resonance assays to determine binding affinity to PA2G4.
  • In vitro assessment of neuroblastoma cell phenotype, apoptosis, and toxicity in myofibroblasts.
  • Evaluation of analogue efficacy in relation to PA2G4 and MYCN expression.

Main Results:

  • Novel WS6 analogues (#5333 and #5338) demonstrated direct binding to PA2G4.
  • These analogues exhibited significantly lower toxicity (70-fold) to normal human myofibroblasts compared to WS6.
  • Structure-activity relationship analysis identified optimal substituents for enhanced efficacy and selectivity.
  • WS6 analogues inhibited neuroblastoma cell phenotype in vitro, dependent on PA2G4 and MYCN.

Conclusions:

  • Chemical inhibition of the PA2G4-MYCN interaction via WS6 analogues is a promising first-in-class drug discovery strategy.
  • These analogues offer a potential therapeutic avenue for neuroblastoma and other MYCN-driven cancers.
  • The reduced toxicity profile suggests improved therapeutic index for clinical translation.
Keywords:
MYCNPA2G4WS6inhibitorsneuroblastoma

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