University of Pittsburgh

Georgetown University

Edward V Prochownik

Steven J Metallo

John S Lazo

Christine Giap

Xiaoying Yin

Ariele Viacava Follis

Provided herein are compounds and compositions for interfering with the association of Myc and Max. These compounds and compositions are useful in methods for inhibiting growth or proliferation of a cell. Methods of inhibiting growth or proliferation of a cell comprise contacting the cell with an amount of a compound that interferes with Myc and Max association effective to inhibit growth or proliferation of the cell.

Linked Myc-max small molecule inhibitors

Compounds and compositions for interfering with the association of Myc and Max are described herein. These compounds and compositions are useful in methods inhibiting growth or proliferation of a cell. Methods of inhibiting growth or proliferation of a cell are provided, comprising contacting the cell with an amount of a compound that interferes with Myc and Max association effective to inhibit growth or proliferation of the cell.

Low molecular weight Myc-max inhibitors

The c-Myc oncoprotein, a helix-loop-helix-leucine zipper (HLH-ZIP) transcription factor, is frequently deregulated in human cancers. All known functions of c-Myc, including those pertaining to transformation, require that it heterodimerize with another HLH-ZIP protein, Max. Using a high throughput yeast-based assay, we identified seven low molecular weight substances that inhibit c-Myc-Max association. Each compound also prevented this interaction in vitro and inhibited the growth of c-Myc-expressing fibroblasts, although not of fibroblasts lacking c-Myc. Finally, short-term exposure of c-Myc over expressing fibroblasts to several of the compounds markedly reduced their in vivo tumorigenicity. These studies suggest that yeast-based assays can be used to identify inhibitors of protein-protein interactions and that these frequently function in mammalian cells. The signature specificities of each of the c-Myc-Max compounds identified here further suggest synergistic in vivo function.

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Pittsburgh, PA, United States of America

Edward V Prochownik