New Entities (NE Program)
Zyxin
BioAlliance has decided to explore angiogenesis in order
to identify new targets and new drugs. In this effort, BioAlliance
has selected two different cellular levels to fight the invasiveness
of angiogenesis, one with an extra cellular target (AMEP-cell
to cell interaction described in a separate section) and the
other with an intracellular target (utilizing Zyxin- phenotypic
reversion to restore the cytoskeleton architecture) described
below.
The work on this project is being conducted in co-operation
with Professor Christian Auclair at the Ecole Normale Supérieure
(CNRS) at Cachan and Professor Michel Perricaudet at the Gustave
Roussy Institute.
Based on fundamental work by Professor Auclair project utilized
microarray technology has to identify a key gene (Zyxin).
For this gene, reduction in expression is directly responsible
for the acquisition of the tumor phenotype
The under-expression of this gene leads to a strong modification
of the dynamics of actin polymerization resulting in a loss
of cell-cell membrane interactions and cytoskeleton transformation.
These observations led to the development of a pharmacological
project to identify compounds able to reconstitute actin networks
in tumoural phenotypes under-expressing Zyxin. A pharmacological
target was identified in this context: F- actin.
BioAlliance and the academic team have developed and validated
an actin polymerisation screening test (involving the zyxin
protein role and measuring regulation of actin polymerization)
and a phenotypic cellular test. These tools allow for the
selection and evaluation of candidates for development.
Established
proof of concept and screening tool:
Phenotypic reversion
Loss of Zyxin expression
=
tumoural phenotype
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Restore Zyxin expression
=
loss of tumoural phenotype
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The concept was validated by the observation that a compound
(stabilizing F-actin cyclic protein) restored cell-to-cell
interactions at a non-cytotoxic concentration (<10nM) and
displays a marked anti-tumour activity in vivo, in nude mice
at very low doses. This work has identified new anti-tumour
drugs acting by a completely new non-toxic mechanism inducing
the reversion of the tumoural phenotype.
In a collaborative effort with academic and private partners
we have started testing a library of compounds. The next development
stages will include selecting and optimizing one lead among
the evaluated molecules and then to start preclinical development.
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