2. Academic Validation
  3. Inhibitors of the Oncogenic PA2G4-MYCN Protein-Protein Interface

Inhibitors of the Oncogenic PA2G4-MYCN Protein-Protein Interface

  • Cancers (Basel). 2023 Mar 17;15(6):1822. doi: 10.3390/cancers15061822.
Hassina Massudi 1,  Jie-Si Luo 1 2,  Jessica K Holien 3 4,  Satyanarayana Gadde 1,  Sukriti Krishan 1,  Mika Herath 1,  Jessica Koach 1,  Brendan W Stevenson 4,  Michael A Gorman 4 5,  Pooja Venkat 1,  Chelsea Mayoh 1 6,  Xue-Qun Luo 2,  Michael W Parker 4 5,  Belamy B Cheung 1 6,  Glenn M Marshall 1 7
Affiliations

Affiliations

  • 1 Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2750, Australia.
  • 2 Department of Paediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510060, China.
  • 3 School of Science, STEM College, RMIT University, Melbourne, VIC 3000, Australia.
  • 4 ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
  • 5 ACRF Facility for Innovative Cancer Drug Discovery, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia.
  • 6 School of Women's and Children's Health, UNSW Sydney, Sydney, NSW 2750, Australia.
  • 7 Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW 2031, Australia.
PMID: 36980710 DOI: 10.3390/cancers15061822
Abstract

MYCN is a major oncogenic driver for neuroblastoma tumorigenesis, yet there are no direct MYCN inhibitors. We have previously identified PA2G4 as a direct protein-binding partner of MYCN and drive neuroblastoma tumorigenesis. A small molecule known to bind PA2G4, WS6, significantly decreased tumorigenicity in TH-MYCN neuroblastoma mice, along with the inhibition of PA2G4 and MYCN interactions. Here, we identified a number of novel WS6 analogues, with 80% structural similarity, and used surface plasmon resonance assays to determine their binding affinity. Analogues #5333 and #5338 showed direct binding towards human recombinant PA2G4. Importantly, #5333 and #5338 demonstrated a 70-fold lower toxicity for normal human myofibroblasts compared to WS6. Structure-activity relationship analysis showed that a 2,3 dimethylphenol was the most suitable substituent at the R1 position. Replacing the trifluoromethyl group on the phenyl ring at the R2 position, with a bromine or hydrogen atom, increased the difference between efficacy against neuroblastoma cells and normal myofibroblast toxicity. The WS6 analogues inhibited neuroblastoma cell phenotype in vitro, in part through effects on Apoptosis, while their anti-cancer effects required both PA2G4 and MYCN expression. Collectively, chemical inhibition of PA2G4-MYCN binding by WS6 analogues represents a first-in-class drug discovery which may have implications for Other MYCN-driven cancers.

Keywords

MYCN; PA2G4; WS6; inhibitors; neuroblastoma.

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