The transcriptional regulator MYC was first discovered more than three decades ago, and has since been identified as an oncogenic driver in a wide variety of the most aggressive human malignancies. As a pleiotropic transcriptional regulator, MYC directly or indirectly controls expression of hundreds of coding and noncoding transcripts. Genes under MYC control affect cell cycle entry, proliferation, differentiation, metabolism, and death/survival decisions in normal and transformed cells. Despite its prevalence, there is no current clinically-available therapeutic strategy to treat tumors with aberrant MYC expression. We have identified a unique and selective inhibitor of the MYC protein that is able to attenuate MYC-driven cellular proliferation and reduce the tumor burden of xenograft mice without acute toxicity. We will present initial SAR studies that have resulted in new equipotent inhibitors, which are of significantly increased solubility and potentially better pharmacokinetics. Also discussed will be biophysical characterization of these inhibitors, which has led to a better understanding of the mechanism of MYC inhibition, and revised strategies for targeting this elusive oncogene.

Preclinical development and characterization of MYC inhibitors

253rd National Meeting (2017)

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