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Stabilizers of the Max homodimer identified in virtual ligand screening inhibit Myc function

Hao Jiang1, Kristen E Bower, Albert E Beuscher

  • 1Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. hjiang@scripps.edu

Molecular Pharmacology
|June 6, 2009
PubMed

Insights

Researchers found a compound that stabilizes the Max homodimer, reducing the activity of the Myc oncoprotein. This discovery offers a new therapeutic strategy for targeting Myc-driven cancers.

Area of Science:

  • Molecular Biology
  • Oncology
  • Drug Discovery

Background:

  • The Myc oncoprotein is frequently overexpressed in human cancers, making it a significant therapeutic target.
  • Myc function relies on its dimerization with Max, which is constitutively expressed and forms unstable homodimers.

Purpose of the Study:

  • To down-regulate Myc activity by targeting its essential dimerization partner, Max.
  • To identify small molecules that stabilize the Max homodimer, thereby disrupting Myc-Max heterodimerization.

Main Methods:

  • Virtual ligand screening (VLS) was employed to identify potential small molecule binders for Max homodimer pockets.
  • Candidate compounds were screened using fluorescence resonance energy transfer (FRET).
  • In vitro binding assays confirmed the compound's effect on Max homodimerization and Myc-Max heterodimerization.

Main Results:

  • A potent and specific stabilizer of the Max homodimer was identified.
  • The compound dose-dependently enhanced Max-Max homodimer formation and inhibited Myc-Max heterodimerization.
  • This Max-Max stabilizer interfered with Myc-induced oncogenic transformation, cell growth, and transcriptional activation.

Conclusions:

  • Stabilizing the Max homodimer is an effective strategy to inhibit Myc activity.
  • The identified Max-Max stabilizer serves as a lead compound for developing novel inhibitors of the Myc network.
  • This approach holds promise for therapeutic interventions in Myc-driven cancers.

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