title: Stabilizers of the Max homodimer identified in virtual ligand screening inhibit Myc function.
abstract: Many human cancers show constitutive or amplified expression of the transcriptional regulator and oncoprotein Myc, making Myc a potential target for therapeutic intervention. Here we report the down-regulation of Myc activity by reducing the availability of Max, the essential dimerization partner of Myc. Max is expressed constitutively and can form unstable homodimers. We have isolated stabilizers of the Max homodimer by applying virtual ligand screening (VLS) to identify specific binding pockets for small molecule interactors. Candidate compounds found by VLS were screened by fluorescence resonance energy transfer, and from these screens emerged a potent, specific stabilizer of the Max homodimer. In vitro binding assays demonstrated that the stabilizer enhances the formation of the Max-Max homodimer and interferes with the heterodimerization of Myc and Max in a dose-dependent manner. Furthermore, this compound interferes with Myc-induced oncogenic transformation, Myc-dependent cell growth, and Myc-mediated transcriptional activation. The Max-Max stabilizer can be considered a lead compound for the development of inhibitors of the Myc network.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. hjiang@scripps.edu
authors.forename: Hao
authors.initials: H
authors.lastname: Jiang
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Bower
authors.forename: Albert E
authors.initials: AE
authors.lastname: Beuscher
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Bobkov
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Olson
authors.forename: Peter K
authors.initials: PK
authors.lastname: Vogt
mesh_terms: D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000187:drug effects* / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA; D004354:Drug Screening Assays, Antitumor; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D008024:Ligands; D011487:Protein Conformation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D008024:Ligands; C499330:MAX protein, human; D016271:Proto-Oncogene Proteins c-myc; D054852:Small Molecule Libraries; D004247:DNA