Project: Drug discovery service platform targeting the human kinome for the treatment of cancer, diabetes and inflammation

Aim of the project_x000D_The expertise of three SMEs will be combined to create a service platform and launch "off-the-shelf" three-dimensional structures of protein kinase targets and their complexes with small-molecule fragments. These structures will have the potential to serve as a starting point for development of lead compound and candidate drugs for the treatment of serious human disorders such as cancer, autoimmune diseases, diabetes, osteoporosis and metabolic diseases. By providing the pharmaceutical industry with off-the shelf three-dimensional structures of kinases and their complexes with novel compounds, we will contribute to a considerable acceleration of the drug discovery process. _x000D__x000D_Background_x000D_Only 0.1% of all lead compounds in drug discovery projects eventually enter phase I clinical trials. This high "attrition rate" has created extreme pressure on pharmaceutical companies to find new and cheaper solutions in the drug discovery process. Thus, new approaches, chemical tools and technologies are urgently required to save money and time in drug discovery and development. One solution is outsourcing of the early stages of the drug discovery process, which is often associated with large investments in infrastructure and expertise. One of these early stages is the determination of the three-dimensional structure of the protein of interest, which dramatically reduces the amount of time (and costs) needed for the design of a new drug. This demand has led to the establishment of several companies offering expertise in the area of structure-based drug discovery (SBDD). As part of their total portfolio of services, these companies often offer their own products in the form of “off-the-shelf” three-dimensional structures of protein targets. These can within a short period of time be co-crystallised with customers' compounds, revealing the mode of interaction of the compound with the protein target._x000D__x000D_In an effort to identify new business opportunities, KinaseDetect, IOTA Pharmaceuticals and SARomics Biostructures, each with world-class expertise in its specific area, have created a strategic alliance to extend their services to include “off-the-shelf” three-dimensional structures of kinases involved in cancer, diabetes and inflammation, as well as their complexes with small-molecule fragments with potential use in SBDD. KinaseDetect is a biotechnology company based in Odense, Denmark, with a focus on provision of highly purified recombinant human protein kinases, substrates and assays. IOTA Pharmaceuticals, in Cambridge, UK, offers industry-leading fragment-based drug discovery capabilities. SARomics Biostructures is a contract research company based in Lund, Sweden, offering services in the areas of computational chemistry, protein crystallization, protein structure determination by X-ray crystallography and NMR spectroscopy._x000D__x000D_Deficiency in protein kinase activity has implications in serious human disorders such as cancer, autoimmune diseases and immunosuppression, diabetes, osteoporosis and various metabolic dysfunctions. This places protein kinases among the top targets for the pharmaceutical industry. The first small-molecule kinase inhibitor approved for use in humans was Imatinib, which has dramatically changed the prognosis for patients with chronic myeloid leukaemia. Recently about 20 different kinase inhibitors have been approved, primarily for the treatment of various cancer forms, and further compounds are in clinical trials for treatment of diabetes, rheumatoid arthritis and cancer. Currently around 40 three-dimensional kinase structures are offered “off the shelf” on the European and American markets. Many new kinases are also being identified as potential targets for the treatment of cancer, diabetes and inflammation, although these have not yet found their way to the “off-the shelf” market. _x000D__x000D_Based on the market situation, we have agreed on the following specific aims of the KINOMED project:_x000D__x000D_1 Cloning, expression and purification of the kinase targets_x000D_2 Establishing enzymatic assays for these kinases_x000D_3 Construction of novel fragment and compound libraries for the targeted kinases_x000D_4 Determination of the three-dimensional structure of the kinases in free form and in complex with small-molecule fragments_x000D__x000D_The end products will be:_x000D_1 Three-dimensional structures of protein kinases in their apo forms and in complex with bound small molecule fragments. While the structures will be used for co-crystallisation of the customer’s lead compounds and inhibitors, the small-molecule fragment complexes may be sold or leased to pharmaceutical companies interested in their further development into drug candidates._x000D_2 An established service network for kinase production and enzyme assays, biophysical characterisation of the proteins, X-ray structure determination, inhibitor screening and design and medicinal chemistry services._x000D__x000D__x000D_

Acronym	KINOMED (Reference Number: 5156)
Duration	01/03/2010 - 28/02/2013
Project Topic	This primary aim is to create a technology platform allowing us to be a key strategic P for pharmaceutical SME in the development of new small-molecule drugs targeting protein kinases. At the end of the project up to 10 new protein kinase structures will be offered as "off-the-shelf" products.
Project Results (after finalisation)	We have cloned, expressed and purified 7 kinase targets. 2 of them have been sucessfully used by our Ps for co-crystallization and fragment-based library screening.
Network	Eurostars
Call	Eurostars Cut-Off 3

Project partner

Number	Name	Role	Country
3	IOTA Pharmaceuticals Ltd	Partner	United Kingdom
3	KinaseDetect ApS	Partner	Denmark
3	SARomics Biostructures AB	Coordinator	Sweden