Development of an anti-Myc drug has been the focus of research toward creation of cancer therapeutics. Myc is a transcription factor that can become an oncoprotein; dysregulated Myc expression is involved in &gt;50% of all cancers. Max is a transcription factor that heterodimerizes with Myc and regulates Myc activity. The Myc/Max heterodimer binds to the E-box DNA target (CACGTG) and can upregulate a network of genes in uncontrolled manner. Thus, the Myc/Max:E-box network can be considered an oncogenic switch. We used rational design and phage-assisted continuous evolution (PACE) on our designed minimalist protein ME47, which comprises 66 amino acids and suppresses tumor growth in cell culture and in mouse xenograft models. Intriguingly, mutations were uncovered that were not anticipated, including those that led to a better folded, more robust version of ME47. Moreover, the E-box also governs transcription of plasminogen activator inhibitor 1 (PAI-1), which is critical in the development of asthma. Given that asthma is the most common chronic disease among children and that over half of asthma patients in N. America do not have control of their asthma, we have focused on design of small dimers that target E-boxes involved in asthma. We will discuss our PACE system and development of minimalist protein dimers that target E-boxes in cancer and asthma.

Rational design & directed evolution of small protein dimers: Inhibiting Myc in cancer and PAI-1 in asthma

2019 Fall National Meeting

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