ASSESSING THE THERAPEUTIC WINDOW FOR FUTURE ANTI-NOTCH DIMERIZATION AGENTS

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DESCRIPTION (provided by applicant): Aberrant Notch signals have been linked to cancer and other human diseases, which has motivated the pharmaceutical industry to develop agents inhibiting Notch signaling. However, studies in the mouse predicted that these agents would be toxic to various organ systems. Confirmed in humans are toxicities to the gastrointestinal track and skin, the latter leading to elevated rates of non-melanoma skin cancer. We have shown that targeting Notch1 specifically will result in vascular tumors in addition to increasing cancer rates in the skin; if this will occur in humans it will limit the therapeutic potential of anti-Notch1 therapies in a chronic disease setting. Recently, we and our collaborators reported that dimerization of active Notch molecules is an important step in the activation of some target genes and is required for the oncogenic activity of Notch1 in T-cell leukemia (T-ALL). The absolute dependence of T- ALL on Notch dimerization provides a novel mechanism-based therapeutic avenue. However, the biological consequences of targeting this aspect in Notch signaling are currently unknown due to novelty of the observation and the lack of tools that can differentiate dimerization-dependent from -independent targets. We were fortunate to be awarded ARRA funds to develop a new technology that can interrogate target selection by different multi-member complexes using complementing fragments of the E. coli DNA Adenine methyltransferase (DAM). It is an ideal novel method to identify Notch dimerization dependent targets. In this application we propose to facilitate drug development efforts for 'dimer-busting' therapeutics by defining the therapeutic window (the spectrum of untoward effects in vivo), by identifying dimerization dependent targets (should this window prove to be too narrow or the drug discovery efforts too difficult) and by utilizing our dimer-sensitive assay and high throughput screening to identify drug leads.