Targeting MYC: From understanding its biology to drug discovery

The MYC oncogene is considered to be a high priority target for clinical intervention in cancer patients due to its aberrant activation in more than 50% of human cancers. Direct small molecule inhibition of MYC has traditionally been hampered by its intrinsically disordered nature and lack of both binding site and enzymatic activity. In recent years, however, a number of strategies for indirectly targeting MYC have emerged, guided by the advent of protein structural information and the growing set of computational tools that can be used to accelerate the hit to lead process in medicinal chemistry. In this review, we provide an overview of small molecules developed for clinical applications of these strategies, which include stabilization of the MYC guanine quadruplex, inhibition of BET factor BRD4, and disruption of the MYC:MAX heterodimer. The recent identification of novel targets for indirect MYC inhibition at the protein level is also discussed.