Engineering NK1 as a MET
antagonist for cancer therapy
Dr Ermanno Gherardi
University of Cambridge
There is considerable evidence,
both pre-clinical and clinical, involving the growth factor HGF/SF
and its receptor MET [1,2] in invasion and metatasis of prostatic
carcinoma cells. There is also proof of concept that fragments of
HGF/SF that behave as partial MET antagonist can abolish in
vitro invasion of prostatic carcinoma cells. The aim of this
project is to engineer fragments of the polypeptide growth factor
HGF/SF, such as NK1, as receptor antagonists for cancer therapy.
The work builds on on the structure and mechanism of activity of
NK1, the receptor binding fragment of HGF/SF.
The crystal structure of
NK1 shows a head to tail dimer with an extensive interprotomeric
surface (Fig. 1) .
NK1 requires heparan sulphate
for activity and the same dimer is found in crystal structures of
NK1-heparin complexes . Heparin binds predominantly to the N-domain
but also makes several contacts with the K1 domain (Fig. 2).
For engineering NK1 as
a MET antagonists we are following several strategies. The first
of these involves re-engineering of the linker connecting the N
and K1 domain because the linker plays an important role in the
packing of the NK1 dimer and may control the formation of the NK1
dimer itself via domain swapping . Additional approaches
are also explored which rely on engineering fragments of HGF/SF
containing combinations of kringle domains but lacking the N domain.
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