Overexpression of the MYC oncogene, which encodes a master regulator transcription factor, is causally associated with most types of human malignancies. The Myc protein governs transcription of thousands of gene products involved in regulating key cellular programs, including growth, self-renewal, differentiation, angiogenesis, and host immune response. Inactivation of Myc in model systems or using a dominant negative peptide appears to elicit oncogene addiction and tumor regression. Inactivation of Myc-driven transcriptional programs using small molecules may provide a general approach to treating a broad swath of cancers as Myc is one of the most common drivers of malignancy. Despite intense effort, no clinical Myc-directed therapies exist and there is a need to explore new strategies to alter deregulated Myc-driven transcriptional programs in cancer. A strategy involving attenuation of Myc-amplified programs by modulating the obligate heterodimer partner Max with small molecules will be described. The heterodimer activates transcription while the homodimer competes for the same genomic target sites and represses transcription. Max is thought to be a tumor suppressor based on observations involving the contributions of inactivating Max mutations to tumorigenesis in sporadic human pheochromocytoma and small cell lung cancers. An emerging hypothesis is that the tumor suppressor activity of Max relies on its ability to modulate Myc-driven programs via the homodimer. The small molecule, KI-MS2-008, binds to Max and stabilizes the Max homodimer. The compound reduces c-Myc protein levels in cells and modulates Myc-driven transcriptional programs in engineered and non-engineered cells. Chromatin immunoprecipitation coupled to sequecing (ChIP-seq) reveals that compound treatment decreases c-Myc protein binding and increases Max protein binding at promoters of Myc-occupied genes. The compound displays anti-tumor activities in vitro and in vivo using engineered and non-engineered systems. Efforts focused on characterizing the molecular and cellular mechanisms of action through biophysical, structural, and proteomics studies will be described.

Attenuating oncogenic transcription with small molecules

2019 Spring National Meeting

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