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Innovative inhibitors of Notch trafficking and signalling for the treatment of cancer

Reference Number TO 11-00054

Challenge

The Notch signaling pathway plays a key role in development and cell-fate determination while its aberrant activity has been found to lead to developmental disorders and cancer. At present, therapeutic interventions of aberrant Notch signaling, for example in cases of T cell-lineage acute lymphoblastic leukemia (T-ALL), are aimed at the process of ligand-binding and gamma-secretase cleavage. Several inhibitors of the gamma-secretase (GSI) were already tested for their anti-cancer activity but failed due to significant side effects. Therefore, identification of novel compounds targeting additional trafficking and regulation steps in Notch signalling would be highly desired and could provide promising new therapeutic strategies. 

Overview of trafficking and processing of Notch∆E-EGFP and target of identified compounds.
Overview of trafficking and processing of Notch∆E-EGFP and target of identified compounds.

Technology

The invention relates to five novel compounds (FLI-6, FLI-14, FLI-15, FLI-19, FLI-20)  as potential inhibitors of the notch signalling pathway for the treatment of cancer. These compounds address different steps in trafficking and regulation of Notch signalling. FLI-6 acts on a very early step in recruitment of cargo to endoplasmic reticulum exit sites and therefore affects the general transport through the secretory pathway. FLI-15 and -20 are novel direct GSIs whereas FLI-14 and -19 inhibit Notch and amyloid precursor protein (APP) processing in cells. Therefore these compounds can be promising starting points for the development of innovative anti-cancer therapeutics.

Commercial Opportunity

The technology is offered for co-development or in-licensing.

Developmental Status

All compounds were validated in in vitro and cellular assays using C2C12 cells as well as in vivo in a well-established zebrafish model.

Patent Situation

Priority was filed 2011. PCT applicaton was filed in 2013 (WO2013178821). Patent applications pending in EP, USA and JP.

Further Reading

Krämer et al. Small molecules intercept Notch signalling and early secretory pathway. Nat. Cem. Biol. 2013 Sep 29. doi: 10.1038/nchembio.1356.