Available Technology
Modulators of notch dimerization and receptor signalling
Technology:
Novel therapeutic target
Markets Addressed
Targeting the extracellular domain of a membrane receptor is an attractive strategy for drug development. The Notch extracellular domain may be an important, novel therapeutic target for cancers as well as some genetic disorders:
• Cancer: Dysregulation of Notch signaling has been shown in hematological cancers, such as leukemia and lymphoma, as well as solid tumors, such as skin, breast, lung, pancreas, colon and brain tumors. Notch inhibitors may also help to eliminate Cancer Stem Cells, master tumor cells that often resist chemo- and radiotherapy and give rise to new tumor bulk when cancer relapses. Such therapeutics may be a novel strategy for the treatment of advanced cancers, for example stage III and IV breast cancer and certain types of T cell leukemia.
• Notch-related hereditary disorders: Several severe genetic disorders are caused by mutations in Notch genes, including pleiotropic congenital syndromes and the stroke disorder CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). CADASIL is one of the most common forms of hereditary stroke disorder; current therapy is symptomatic and no development of a targeted drug has been announced.
Innovations and Advantages
Notch transmembrane receptor plays an important role in cell-cell communication and is involved in a variety of processes, including development of nervous and circulatory systems, bone development and T-cell lineage commitment. Many cancers are characterized by upregulated Notch signaling and mutations in Notch pathway proteins are causes of several genetic disorders.
The primary, transmembrane structure of this novel therapeutic target was determined over two decades ago. Additional structural information has been obtained for the intracellular domain which, upon ligand binding, is cleaved and translocates to the nucleus where it participates in transcriptional events. However, very little information is available about the tertiary and quaternary structure of the Notch extracellular domain (NECD), important for developing a therapeutic to interfere with Notch function.
Using electron microscopy, Drs. Artavanis-Tsakonas and Walz obtained detailed structural information for the NECD. They discovered that the NECD adopts specific conformations, and identified three 3D structures that are highly conserved from fly to human. In addition, the researchers discovered that the NECD forms a homodimer. This implies that the disruption of this quaternary structure can affect the function of the receptor, offering the possibility to identify a novel class of molecules capable of disrupting or enhancing Notch dimerization and hence modulate its signaling function.
Future efforts will focus on functional analysis of different Notch conformations and will link pathological Notch mutations with structural changes in the protein.
Additional Information
This technology is available for worldwide, exclusive licensing and/or a collaborative research program with the Artavanis-Tsakonas and Waltz laboratories.
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Inventor(s):
Artavanis-Tsakonas, Spyros
Kelly, Deborah F.
Lake, Robert
Walz, Thomas
Categories:
For further information, please contact:
Geff Erickson, Director of Business Development
(617) 432-0920
Reference Harvard Case #3681