摘要：MYC is a transcriptional regulator that in order to function has to dimerize with a specific partner protein, MAX. The MYC-MAX dimer regulates the expression of thousands of genes involved in fundamental cellular processes including growth, proliferation, differentiation, biosynthesis, energy metabolism, and apoptosis [1-3]. The discovery that MYC becomes overexpressed as a result of chromosomal re- arrangements in Burkitt's lymphoma was the first implication of MYC in human cancer, and today deregulated MYC expression is considered to be the crucial driving force in most if not all cancers [1-3]. Because of this prevalent role in carcinogenesis, MYC is an important target for therapeutic intervention. However, there are both principal and practical obstacles in targeting MYC. Inhibition of a gene that is essential for fundamental cellular processes could cause unacceptable side effects. Yet inhibition of MYC by expression of a dominant-negative MYC construct in an animal model caused regression of tumor growth but no lasting damage to rapidly proliferating normal tissues [4]. Practical problems in directly targeting MYC or the MYC-MAX heterodimer with small molecules (Figure 1) stem from the disordered state of the MYC monomer in solution and from the general nature of protein- protein interactions. These commonly involve large interacting surfaces that present no well-defined pockets or grooves for high-energy binding of small ligands. However, proof of principle for overcoming these difficulties was provided by the identification of small- molecule antagonists for MYC-MAX dimerization that reduced MYC-driven cell transformation in tissue culture [5].
