Myc activity can be deregulated through increased expression by either gene amplification or gene translocation . In more limited cases, particularly in Burkitt��s Lymphoma, the Myc gene is mutated which can result in a more stable protein . To function biologically, Myc forms a heterodimer with its partner Max, and the resulting dimer binds to specific promoter motifs, recruits transcription activation complexes, and ultimately activates Myc-dependent genes. It is clear that inactivation of Myc can lead to significant anti-tumor effects in mouse models of cancer . In addition, functional inactivation of Myc in normal tissue using a dominant negative form is well tolerated , supporting the concept that therapeutically targeting this pathway can be a means to treat cancer. Numerous direct and indirect methods have been 1370468-36-2 supplier developed to target Myc biology . Recently small molecules that inhibit the BET family of epigenetic reader proteins and impact Myc gene expression have shown excellent pre-clinical efficacy in Myc-dependent tumor models and are currently in clinical trials. Microcystin-LR Several groups have also reported small molecule inhibitors that bind directly to Myc and inhibit its interaction with Max . These inhibitors, originally introduced by Prochownik et al, bind with micromolar affinity and disrupt the Myc:Max interaction, as well as inhibit proliferation of Myc-expressing tumor cell lines. Two such small molecules, 10058-F5 and 10074-G5, have been shown to bind independently and simultaneously to the disordered conformation of the basic helix-loop-helix leucine zipper domain of Myc, thus inhibiting its interaction with Max . Additionally, close analogs of 10058-F4 and 10074-G5 with similar and improved potencies have been described . We have utilized our technology platform to develop self-assembling dimeric inhibitors of Myc using these previously described small molecules as our starting individual ligands. These molecules are additionally modified with appended connectors and linkers designed to facilitate reversible dimer formation. We demonstrate that our new inhibitors directly bind to Myc with improved affinity over the existing small mole