Targeting Protein Kinases

Targeting Protein-Kinases

The protein kinase family offers a challenge but also a huge opportunity for drug discovery. About 22% of the druggable human genome codes target protein kinases. Approximately 30% of all marketed drugs target G-protein-coupled receptors, about 7% address ion channels and roughly 4% bind to nuclear hormone receptors. There are, however, only few drugs (wourldwide 7 registered drugs, e.g. Gleevec ®, Iressa ®) on the market that address protein kinase targets. Kinases regulate many different cell proliferation, differentiation, and signalling processes by adding phosphate groups to target protein substrates. Reversible protein phosphorylation is the main strategy for the control of eukaryotic cell activities. Disease arises when signal transduction in a cell breaks down, thereby removing the tight control that typically exists over cellular functions. Devastating diseases such as cancer, autoimmune diseases, inflammation, psoriasis, allergic reactions, neurological disorders and hormone-related diseases can result from abnormal signal transduction. Expected sales of these novel class of drugs are > 10 Bil USD in the year 2010.
At present 518 kinases are identified, in which all of them bind the cofactor ATP in a very similar way. The conservation of structural features within the ATP binding cleft initially indicated that specificity for ATP-site directed inhibitors would be difficult to achieve. Structure elucidation of ATP complexes bound to protein kinases, have revealed that there are regions within or close to the binding cleft that ATP does not fully occupy. These regions, unoccupied by ATP, show structural diversity between members of the kinase family. This provides opportunities for the discovery or design of selective and small molecule ATP-competitive inhibitors.
These facts dictate a great need for fundamental research in this field and for the development and design of new lead structures targeting protein kinases.
According to latest investment reports, about 28% of all industrial drug discovery programs focus on protein kinases.

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Our group focus on:

Structure-Based Drug Design and Discovery to provide tools, leads and candidates.

Major Kinase-Targets are:

p38 MAP Kinase (alpha and delta)
JNKs (1,2,3)
VEGF-R

Technically, we take an itterative approach:

• generate structural hypothesis based on x-ray structures or homology models of the target kinase
• medicinal chemistry, synthesis of candidates
• in vitro testing in various kinase assays

Selected candidates are profiled in secondary assays:

• Kinase-Profile
• Cell-based assays
• Whole blood assays
• In vitro metabolism including LC-MS analytics
• First ADME testings

Further in vivo studies are performed in collaboration with both academic and industrial partners.