Journal
MOLECULAR CANCER THERAPEUTICS
Volume 6, Issue 9, Pages 2399-2408Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-07-0005
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- NCATS NIH HHS [UL1 TR000005] Funding Source: Medline
- NCI NIH HHS [CA105033, R01 CA140624] Funding Source: Medline
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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.
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