Transferangebote:

  • Anti-metastatic drugs
     
 

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Anti-metastatic drugs

A novel approach to block cancer metastasis based on inhibition of Ena/VASP EVH1 domains

Ansprechpartner

Dr. Birgit Oppmann

Kurzbeschreibung

Background/Application Area

Metastasis formation is a highly complex process, which is initially enabled by the epithelial- mesenchymal transition of cancer cells. This leads to increased directed cellular motility by remodelling of the actin cytoskeleton. Ena/VASP proteins are essential for this process, since they are involved in formation of lamellopodia and filopodia as well as in coupling focal adhesion complexes to F-actin filaments. Their overexpression in non-specific invasive breast cancer cells has made them an interesting drug target. The regulatory function of the Ena/VASP proteins depends on their cellular localization, which is controlled by the supposedly undruggable EVH1 domain. Based on a rationally designed toolkit of new chemical entities mimicking a left-handed polyproline II helix (PPII), for the first time selective small-molecule Ena/VASP-EVH1 inhibitors have been synthesized, which were able to block both, chemotaxis and motility of invasive breast cancer cells. These properties are absolute preconditions for cancer metastasis. The novel compounds exhibit advantageous ADMET properties, e.g. very low toxicity, high stability in liver microsomes as well as in blood plasma, and good solubility.

Furthermore, the extendable and IP-protected toolkit of currently 16 different PPII-mimicking building blocks (PPII toolkit) opens up completely new opportunities for future drug discovery projects addressing hitherto undruggable disease-relevant polyproline motif mediated protein-protein interactions involving more than 1000 human proteins.

Commercial Opportunity

Metastasis Inhibitor

Although over 90% of cancer deaths today are due to metastasis formation yet no anti- metastatic drug has reached the market. The drug discovery projects are mainly focused on inhibition of receptor tyrosine kinases, integrin receptors, matrix metalloproteinases, and focal adhesion kinase. Observation of side effects like disruption of cell-cell contacts or changes in gene expression yielded premature failure of clinical studies. The innovative concept of decoupling cytoskeleton remodeling in response to integrin and receptor tyrosine kinase signaling cascades avoids such consequences.

PPII toolkit

The technology allows to develop selective inhibitors of protein-protein interactions mediated by all classes of proline-rich motif recognizing protein domains like EVH1, SH3, and WW. Many of these domains are involved in regulation of disease relevant signaling cascades. The PPII-toolkit contains without exception new chemical entities with defined stereo chemistry which can be used for design and synthesis of focused libraries.

Detailinformationen (Internetadresse)

http://www.leibniz-fmp.de/technology-transfer/offers.html

 

Anschrift

  • Campus Berlin-Buch
  • Robert-Rössle-Str. 10
  • 13125 Berlin

Ansprechpartner

 
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