title: Improved low molecular weight Myc-Max inhibitors.
abstract: Compounds that selectively prevent or disrupt the association between the c-Myc oncoprotein and its obligate heterodimeric partner Max (Myc-Max compounds) have been identified previously by high-throughput screening of chemical libraries. Although these agents specifically inhibit the growth of c-Myc-expressing cells, their clinical applicability is limited by their low potency. We describe here several chemical modifications of one of these original compounds, 10058-F4, which result in significant improvements in efficacy. Compared with the parent structure, these analogues show enhanced growth inhibition of c-Myc-expressing cells in a manner that generally correlates with their ability to disrupt c-Myc-Max association and DNA binding. Furthermore, we show by use of a sensitive fluorescence polarization assay that both 10058-F4 and its active analogues bind specifically to monomeric c-Myc. These studies show that improved Myc-Max compounds can be generated by a directed approach involving deliberate modification of an index compound. They further show that the compounds specifically target c-Myc, which exists in a dynamic and relatively unstructured state with only partial and transient alpha-helical content.
authors: Section of Hematology/Oncology, Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Huabo
authors: H
authors: Wang
authors: Dalia I
authors: DI
authors: Hammoudeh
authors: Ariele Viacava
authors: AV
authors: Follis
authors: Brian E
authors: BE
authors: Reese
authors: John S
authors: JS
authors: Lazo
authors: Steven J
authors: SJ
authors: Metallo
authors: Edward V
authors: EV
authors: Prochownik
mesh_terms: D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation / Q000187:drug effects*; D019281:Dimerization; D024202:Electrophoretic Mobility Shift Assay; D005453:Fluorescence; D018922:HL-60 Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008970:Molecular Weight; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors*; D012236:Rhodanine / Q000737:chemistry
chemical_list: C416546:5-(4-(4-(diethylamino)butyl)-1-piperidinyl)acetyl-5H-dibenz(b,f)azepine; D001381:Azepines; D050976:Basic-Leucine Zipper Transcription Factors; C067850:Myc associated factor X; D010880:Piperidines; D016271:Proto-Oncogene Proteins c-myc; D012236:Rhodanine