MYC is a highly validated oncogenic transcription factor and cancer target. However, the disordered nature of this protein has made it a challenging target, with no clinical stage, direct small-molecule MYC inhibitors available. Recent work leveraging a large in silico chemical library and a rapid in vivo screen has expanded the chemotypes of direct small-molecule inhibitors (MYCi). Novel MYCi represent a class of improved MYC chemical probes that bind directly to MYC to inhibit its function and to promote its degradation by enhancing GSK3β-mediated phosphorylation. One of these compounds, MYCi975, has shown remarkable tolerability and efficacy in vivo and is associated with a selective effect on MYC target gene expression. Additional effects of MYCi on the tumor immune microenvironment including immune cell infiltration and upregulation of PD-L1 expression provide a rationale for combining MYCi with anti-PD-1/PD-L1 therapy to enhance antitumor efficacy. Our strategy for developing MYCi demonstrates an efficient way to identify selective and well-tolerated MYC inhibitors. The new MYCi provide tools for probing MYC function and serve as starting points for the development of novel anti-MYC therapeutics.
©2020 American Association for Cancer Research.