The Notch pathway is a highly conserved signaling system that plays an important role in development and tissue homeostasis. Inhibition of Notch signaling may provide an attractive targeted cancer therapeutic strategy. We have identified and characterized LY3039478, a novel small molecule that is an exquisitely potent inhibitor of Notch-1 intracellular domian (N1ICD) cleavage with an IC50 of approximately 1 nM in most of the tumor cell lines tested. In a xenograft tumor model, LY3039478 inhibited N1ICD cleavage and expression of Notch-regulated genes in the tumor microenvironment. To mitigate the mucoid gastroentropathy caused by Notch inhibition, PK/PD data were incorporated in devising dosing strategies that identified an optimal intermittent dosing schedule without negatively impacting efficacy. In summary, we have characterized an orally bio-available small molecule Notch inhibitor that may provide therapeutic benefit to cancer patients with deregulated Notch signaling. LY3039478 is specifically designed to potently inhibit Notch signaling and is being investigated in phase 1.

Novel inhibitor of Notch signaling for the treatment of cancer

248th National Meeting (2014)

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