Selective inhibition of c-Myc/Max dimerization and DNA binding by small molecules.
bZip and bHLHZip protein family members comprise a large fraction of eukaryotic transcription factors and need to bind DNA in order to exert most of their fundamental biological roles. Their binding to DNA requires homo- or heterodimerization via alpha-helical domains, which generally do not contain obvious binding sites for small molecules. We have identified two small molecules, dubbed Mycro1 and Mycro2, which inhibit the protein-protein interactions between the bHLHZip proteins c-Myc and Max. Mycros are the first inhibitors of c-Myc/Max dimerization, which have been demonstrated to inhibit DNA binding of c-Myc with preference over other dimeric transcription factors in vitro. Mycros inhibit c-Myc-dependent proliferation, gene transcription, and oncogenic transformation in the low micromolar concentration range. Our data support the idea that dimeric transcription factors can be druggable even in the absence of obvious small-molecule binding pockets.
Kiessling
Anke
A
Department of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.
Sperl
Bianca
B
Hollis
Angela
A
Eick
Dirk
D
Berg
Thorsten
T
D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D017931:DNA Primers; D019281:Dimerization; D016231:Fluorescence Polarization Immunoassay; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
D050976:Basic-Leucine Zipper Transcription Factors; D017931:DNA Primers; C067850:Myc associated factor X; D016271:Proto-Oncogene Proteins c-myc; D004247:DNA