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Rational Design of Small-Molecule Inhibitors of cMyc-Max Protein-Protein Interaction

Lidio Meireles, Gabriela Mustata and Ivet Bahar

 
cMycMax

Secondary structure representation of cMyc-Max heterodimer bound to DNA (PDB: 1NKP).

cMyc is a bHLH-Zip (basic Helix-Loop-Helix Leucine Zipper) transcription factor that promotes the expression of a large number of genes involved in cell proliferation. The fact that cMyc is over-expressed in many cancer types and that its biological activity depends on dimerization with a related protein, Max, makes the cMyc-Max protein-protein interaction an attractive anti-cancer drug target. However, the design of small-molecule cMyc-Max disruptors has been complicated by the lack of a well-defined cavity at the protein-protein interface that could accomodate a drug-like molecule and by the disordered nature of cMyc prior to complex formation with Max as well. Using known cMyc-Max inhibitors, we developed pharmacophore models, which have been used to identify novel classes of cMyc-Max disruptors. In an iterative process, we then use the newly identified inhibitors to refine the pharmacophore models.

 

Related publication: Mustata, G.; Follis, A. V.; Hammoudeh, D. I.; Metallo, S. J.; Wang, H.; Prochownik, E. V.; Lazo, J. S.; Bahar, I. (2009). Discovery of novel myc-max heterodimer disruptors with a three-dimensional pharmacophore model. J. Med. Chem. 52 (5), 1247-50.

 

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