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Research 1: 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.

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.

 

Research 2: Eicosanoids in Inflammation and Cancer

3rd Generation NSAIDs (non steroidal anti-inflammatory drugs)

Rheumatic diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA) are major causes of disability in Western countries, inflammation and pain are the main causes of the progressive and destructive process in OA and RA.

In the current disease management approach, non-steroidal anti-inflammatory drugs (NSAIDs) play an important role. An improvement in the patient’s condition is achieved by the peripheral analgesic effect and the anti-inflammatory action. However, the use of NSAIDs may result in gastro-intestinal side effects, which range from mild symptoms such as dyspepsia and abdominal discomfort to more serious adverse events such as peptic ulcers, life-threatening gastric/duodenal bleeding and perforation.

The commonly accepted mechanism of action of NSAIDs is the inhibition of cyclooxygenase (COX). COX is a key enzyme in the metabolic pathway leading from arachidonic acid to pro-inflammatory prostaglandins and thromboxanes (Figure 1). The inhibition of COX results in a reduced synthesis of prostaglandins and thromboxanes and is the basis for the anti-inflammatory efficacy and probably also for the analgesic activity of NSAIDs.
However, this same COX inhibition also leads to gastro-intestinal adverse effects due to reduction of gastro-protective prostaglandins. This effect is modified by specific inhibition of the COX-2 isoenzyme which, in contrast to the COX-1 isoenzyme, is not expressed in the gastric mucosa under natural conditions
On the other hand, the inhibition of COX leads to a shunt to the 5-lipoxygenase (5-Lox) pathway (Figure 2). 5-LOX is the second key enzyme in the arachidonic acid metabolism and leads to the formation of leukotrienes. Leukotrienes induce gastric lesions and ulceration due to leukocyte adhesion and vasoconstriction in the gastric mucosa.
This shift from the COX pathway to the 5-Lox pathway is an important reason for the poor gastro-intestinal tolerability of NSAIDs.

The dual inhibition of COX and 5-Lox would be expected to achieve better gastro-intestinal tolerability.
Dual inhibitors of COX and 5-LOX may be considered a distinct class of drugs. Dual acting anti-inflammatory drugs (3rd generation NSAIDs) would be expected to combine good anti-inflammatory and analgesic activities with excellent gastro-intestinal tolerability. Several drugs have proven this new principle in preclinical pharmacological and toxicological investigations

ML3000 (INN: Licofelone) is a novel, potent, balanced, competitive inhibitor of both COX and 5-LOX.
ML3000 has succeeded in clinically validating this mechanism of action.