Low molecular weight inhibitors of Myc-Max interaction and function.
c-Myc is helix-loop-helix-leucine zipper (HLH-ZIP) oncoprotein that is frequently deregulated in human cancers. In order to bind DNA, regulate target gene expression, and function in a biological context, c-Myc must dimerize with another HLH-ZIP protein, Max. A large number of c-Myc target genes have been identified, and many of the encoded proteins are transforming. Such functional redundancy, however, complicates therapeutic strategies aimed at inhibiting any single target gene product. Given this consideration, we have instead attempted to identify ways by which c-Myc itself could be effectively disabled. We have used a yeast two-hybrid approach to identify low-molecular-weight compounds that inhibit c-Myc-Max association. All of the compounds prevented transactivation by c-Myc-Max heterodimers, inhibited cell cycle progression, and prevented the in vitro growth of fibroblasts in a c-Myc-dependent manner. Several of the compounds also inhibited tumor growth in vivo. These results show that the yeast two-hybrid screen is useful for identifying compounds that can be exploited in mammalian cells. More specifically, they provide a means by which structural analogs, based upon these first-generation Myc-Max inhibitors, can be developed to enhance antitumor efficacy.
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D050976:Basic-Leucine Zipper Transcription Factors; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D016259:Genes, myc; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D016350:Leucine Zippers; D051379:Mice; D008819:Mice, Nude; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C499330:MAX protein, human; C067850:Myc associated factor X; C068422:Max protein, mouse