A National Centre for Protein Kinase Profiling

Lead Research Organisation: University of Dundee

Abstract

Kinases are the largest family of enzymes present in human beings. They are involved in co-ordinating almost all the body s functions and their deregulation is a cause or consequence of many diseases. For this reason, kinases have become the major drug targets of the 21st Century. Ten drugs that prevent particular kinases from working have been approved for clinical use and have had a huge impact on the treatment of cancer, including one drug that essentially cures a form of leukaemia that previously was rapidly fatal. The purpose of this application is to obtain funding to maintain and improve a novel service that has been set up by the MRC Unit that I direct and which has proved to be of great value in speeding up the development of drugs in this area.

Technical Summary

Protein kinases have become the most studied class of drug target, with 30% of the R&D effort of the pharmaceutical industry now devoted to this topic. The challenge is to develop drugs that inhibit just one or at most a few of the 500 protein kinases encoded by the human genome. To assist this process, the MRC Protein Phosphorylation Unit (MRC-PPU) introduced the idea of kinase profiling in which the specificities of hits identified by screening compound collections are rapidly profiled against a panel that currently comprises 80 protein kinases. This service has proved to be of critical importance to the pharmaceutical industry, has spawned a spin-out company in Dundee (the Upstate division of Millipore) that employs 70 people and created a new industry worth #200 million per annum worldwide. In recent years, the number of academic researchers operating drug discovery programmes has increased enormously and the kinase profiling service of the MRC-PPU has become vital in providing an affordable service for these organisations. The purpose of the application is therefore to provide the funding needed to set up a National Protein Kinase Profiling Centre for the academic community, MRCT and other organisations. Without such support the service to these users will not continue, because the pharmaceutical companies with whom the MRC-PPU collaborate and who have funded the service so far, now wish the funding for this resource to be used by the MRC-PPU to develop new services that are not yet commercially available.

Publications

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Caster DJ (2013) ABIN1 dysfunction as a genetic basis for lupus nephritis. in Journal of the American Society of Nephrology : JASN

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Clark K (2013) Molecular control of the NEMO family of ubiquitin-binding proteins. in Nature reviews. Molecular cell biology

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Cohen P (2013) Kinase drug discovery--what's next in the field? in ACS chemical biology

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Cohen P (2014) The TLR and IL-1 signalling network at a glance. in Journal of cell science

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Emmerich CH (2013) Activation of the canonical IKK complex by K63/M1-linked hybrid ubiquitin chains. in Proceedings of the National Academy of Sciences of the United States of America

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Lin KM (2014) IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation. in Proceedings of the National Academy of Sciences of the United States of America

 
Description 8th World Conference on Waldenstrom's Lymphoma 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact On the evening of August 16th Philip Cohen gave the closing lecture of the 8th International Workshop on Waldenstrom's Lymphoma in the Churchill rooms of the Houses of Parliament in London. Waldenstrom's lymphoma is caused by mutations in the protein MyD88, and 95% of the patients who are afflicted by this disease express the same mutant in which the leucine residue at position 265 is changed to proline. MyD88 is an essential adaptor protein in the signalling networks that are triggered by the binding of bacterial and viral components to Toll-Like Receptors or by the interaction of interleukins 1, 18 and 33 with their receptors.


Philip's talk to an audience that mainly comprised patients with Waldenstrom's lymphoma, their physicians, relatives and friends, focused on how MyD88 was discovered, and its key role in the innate immune system that is vital for protection against infection by microbial pathogens, especially during childhood. He also explained how the hyper-activation of the MyD88-dependent signalling network can lead to autoimmune diseases, such as lupus, and how its constitutive activation caused by the MyD88[Leu265Pro] mutation leads to lymphoma. The talk was followed by a formal dinner in the Churchill rooms, at which Philip and Tricia Cohen were the guests of honour.
Year(s) Of Engagement Activity 2014
 
Description Interview with ZDF (German National Public Broadcasting) Regarding Scottish Referendum 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact ZDF wished to interview Professor Cohen regarding the risks for life sciences in an independent Scotland for their European affairs programme that wished to discuss an economic case for and against independence.


Sir Philip's signature on an open letter and viewpoints expressed, while his own, brought to light in the general public, the potential deleterious impact a 'Yes' vote would have had upon Scottish scientific research funding.
Year(s) Of Engagement Activity 2014
URL http://www.zdf.de/ZDFmediathek#/hauptnavigation/startseite
 
Description New Drugs for the 21st Century 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact "Philip Cohen gave a talk about kinase drug discovery to the Scotland International Group at the Gleneagles Hotel Scotland on Friday November 29th 2013. Entitled "New Drugs for the 21st Century". The audience of 60 included the CEOs and CFOs of 20% of the UK's FTSE 100 companies, the Brazilian and Russian Ambassadors, the former UK Ambassador to the USA, the former Secretary General of NATO), Sir the former head of UK Government Operations, and Scotland's only two billionaires."


Sir Philip's talk stimulated much discussion as he recounted the research being undertaken in Dundee and the potential of many of the targets torwards therapeutic development.
Year(s) Of Engagement Activity 2014
 
Description Scotland: For Richer or Poorer? 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Professor Sir Philip Cohen will be featured on Robert Peston's BBC2 Documentary 'Scotland: For Richer or Poorer' airing tonight at 9pm on BBC2. How will independence affect Dundee's reputation for excellence in life sciences?


Sir Philip's signature on an open letter and viewpoints expressed, while his own, brought to light in the general public, the potential deleterious impact a 'Yes' vote would have had upon Scottish scientific research funding.
Year(s) Of Engagement Activity 2014
URL http://www.bbc.co.uk/iplayer/episode/b049b89z/scotland-for-richer-or-poorer
 
Description Scottish Referendum - Open Letter 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact "A group of eminent Scottish medical experts have warned that independence would seriously damage research funding for Scotland's universities and medical schools.

The open letter from 14 experts, including senior staff from all five of the country's main medical schools, said they had ""grave concerns"" that Scotland's world-leading biomedical and life sciences research would suffer if Scotland ""sleepwalks"" into leaving the UK.

The letter, coordinated by Sir David Carter, a former chief medical officer in Scotland, said Scottish universities did disproportionately well out of the UK's research funding system and from the UK's charitable and medical foundation grants.
"


Sir Philip's signature on an open letter and viewpoints expressed, while his own, brought to light in the general public, the potential deleterious impact a 'Yes' vote would have had upon Scottish scientific research funding.
Year(s) Of Engagement Activity 2014
URL http://www.theguardian.com/politics/2014/may/23/scottish-independence-research-funding-medical-exper...
 
Description Student's important protein discovery could help fight cancer 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Jiazhen Zhang, a research student in Professor Sir Philip Cohen's laboratory at the University of Dundee, has uncovered how the protein complex, called NF-?B, is activated. The results are published in July, 2014.


Research being undertaken in the Cohen lab was discussed by the broader lay community in an effort to share the impact of these studies
Year(s) Of Engagement Activity 2014
URL http://news.stv.tv/tayside/282195-jiazhen-zhang-at-university-of-dundee-publishes-research-on-nf-b/