National Cancer Research Institute South of England
Prostate Cancer Collaborative

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) [3].

Figure 1.

NK1 requires heparan sulphate for activity and the same dimer is found in crystal structures of NK1-heparin complexes [4]. Heparin binds predominantly to the N-domain but also makes several contacts with the K1 domain (Fig. 2).

Figure 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 [5].   Additional approaches are also explored which rely on engineering fragments of HGF/SF containing combinations of kringle domains but lacking the N domain.


[1]  Cooper , C.S., Park, M., Blair, D.G.,et al., (1984) Nature 311 , 29-33.

[2]  Bottaro, D.P., Rubin, J.S., Faletto, D.L., et al. (1991) Science 251 , 802-4.

[3]  Chirgadze, D. Y., Hepple, J. P., Zhou, H., et al (1999). Nat Struct Biol 6 , 72-9

[4]  Lietha, D., Chirgadze, D.Y., Mulloy, B., et al.   (2001). Eur Mol Biol Org J 20 , 5543-55.

[5]  Watanabe,   K., Chirgadze,    D.Y., Lietha , D., et al., J mol Biol   319 , 283-288 (2002)


Collaborative Home Page

Quick Links to other pages
grey = under construction

Aetiology and Genetics

Epidemiological Identification of Families
Genetic Susceptibility
Diet and Environment

Molecular Pathology

Links to Cancer Genome Project
Development of Normal Prostate
Microarray Expression Profiling
Candidate Genes
Novel Telomerase Suppressor Genes
Subtractive Hybridization

Novel Therapies

New Drugs for Prostate Cancer
Intensity Modulated Radiotherapy
Academic Urology Unit
Novel Targets from Cancer Genome Project
Novel Mechanism Based Drugs

Core Resources

Cancer Gene Cloning Lab
Prostate Tissue arrays
Microarray laboratory
Tissue and blood collections

Pilot and Development Funds

Tumor micro-environment in early prostate cancer

Meetings and Seminars

Contact us on Email: Tel: 0208 643 8901 Fax: 0208 770 7290 This page last modified: 4/06/03