The Myc-Max network of transcriptional regulators plays an important role in the control of cell replication, differentiation, and apoptosis. Gain of Myc function is a driving force in numerous human cancers. The activity of the network depends on the formation of dimers between Max and other network proteins. The relative stabilities of these heterodimers are important factors that control and direct network activity. We propose to identify small molecules that stabilize Max-Max and Mad-Max dimers. Stabilizers of Max-Max would make this essential dimerization partner less available for heterodimerization and are expected to cause a general downregulation of the network. Stabilizers of Mad-Max would increase the anti-Myc activity of Mad. Both types of stabilizers will be tested for their therapeutic potential in cancer. Stabilizers will be identified in combinatorial chemical libraries using fluorescence-based assays developed in this laboratory for isolating inhibitors of Myc-Max dimerization (Berg et al. Proc Natl Acad Sci U S A 99, 3830-3835 (2002). The biological effects of Max-Max and Mad-Max stabilizers will be determined in cellular models, testing the functions of Myc. The principle of regulating cellular functions with small molecule stabilizers of protein dimers is also applicable to numerous other cancer-related control elements in the cell that involve the temporary association of a protein with a negative regulator. The proposed work on stabilizers in the Myc-Max network could open the door to a new way of influencing and directing cell growth.
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