14-3-3 inhibition to accelerate wound healing
A novel approach to enhance re- epithelialization speed by disrupting dimeric 14-3-3 protein
Benefits
Current wound healing therapies rely
on
one
of
three
separate
approaches: 1. preventing infection
or, 2. providing an external scaffold
of extra-cellular matrix or, 3. delivery
of growth factors to promote
epithelial proliferation. Our novel
approach to facilitate rapid wound
healing takes advantage of a
mechanism
we
have
newly
discovered to enhance mitogenic
signaling and promote endogenous
ECM production, using inhibition of
14-3-3.
This approach uses a novel class of
14-3-3 inhibitors that disrupts 14-3-3
dimers in a manner that is not reliant
on competing with the binding of 143-3’s
phospho-serine
containing
client proteins.
Background
14-3-3 proteins act as adaptor
proteins
to
regulate
signaling
pathways
that
promote
cell
proliferation and cell survival, acting
as obligate dimers. The 14-3-3ζ
isoform is one of the dominant
isoforms expressed in skin and is
upregulated significantly in chronic,
non-healing wounds such as diabetic
ulcers.
Furthermore, mice deficient in 14-33ζ exhibited rapid wound healing that
was 3-fold faster than that observed
in normal control mice.
14-3-3ζ acts to restrain the activation
of Rho-ROCK signaling at wound
margins, thereby moderating the
production and remodeling of extracellular
matrix
(ECM).
Reestablishment of damaged ECM is a
key requirement in wound healing as
it performs a scaffolding role to
support re-epithelialization of the
wound and also initiates mechanical
signaling pathways required for
epidermal
cell
proliferation.
Consequently,
inhibiting
14-3-3
activity is an attractive approach to
enhance wound healing in chronic
wounds.
Technology
We used a novel class of molecules
that mimic the binding of sphingosine
lipid to 14-3-3 at the dimer interface,
thereby permitting kinases to access
a buried phosphorylation site,
phosphorylation of which inhibits 143-3 dimerisation. Our studies have
revealed that inhibiting 14-3-3 by
using
these
novel
molecules
accelerates wound healing in a
murine
model,
phenocopying
observations in 14-3-3ζ deficient
animals.
ROCK activation causes
epidermal thickening
Samuel et al., Cancer Cell
19, 776-791 (2011)
For further information, please contact:
Ben Atcliffe, PHD, MBA
Commercial Manager
[email protected]
T: +61 8 8302 5477
M: +61 407 094 660
UniSA Ventures Pty Ltd
PO Box 546, Salisbury South, 5106
Mawson Lakes Campus, GP1-15
www.unisa.edu.au/unisaventures
Potential Markets
We
are
currently
developing
pharmacological inhibition of 14-3-3
with the intent of establishing a novel
modality for the treatment of chronic
wounds.
IP Status
PCT patent application filed for
‘Modulators of 14-3-3 Functionality
and Uses Thereof’ as specification
PCT/AU2015000605.
Partnering Opportunities
We are seeking co-development
partners and technology licensees for
the further development of this
opportunity.
Inventor/s



Dr Michael Samuel, Centre for
Cancer Biology
Professor Angel Lopez, Centre
for Cancer Biology, SA
Pathology
Dr Joanna Woodcock, Centre for
Cancer Biology, SA Pathology