TAKTIC

Translational Kinase Tumour Inhibitor discovery Consortium

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 Obiettivo del progetto (Objective)

'Protein kinases are involved in the control of a large number of cellular processes and play a central role in human physiology. More than 500 genes encoding protein kinases have been identified in the human genome, and it is estimated that about 30% of all human proteins may be phosphorylated by kinases. Deficiency in kinase activity has implications in cancer, central nervous system disorders, autoimmune diseases and immunosuppression, diabetes, osteoporosis and various metabolic disorders. Small-molecule kinase inhibitors have therefore moved into the focus of the pharmaceutical industry as a new class of drugs, which is expected to produce new and more efficient treatments and grow significantly within the coming decade.

The proposed project brings together the unique and proprietary technologies of three SMEs and the expertise of academic research partners to create a new platform for lead compound discovery with a focus on protein kinases. Three kinases will be targeted for the development of inhibitory compounds. The academic partners will contribute a modern high throughput platform for protein expression and crystallisation (Israel Structural Proteomics Centre), and expertise in the biochemistry and biology of the targeted kinases combined with the principles of the use of bioisosterism in synthesis of novel chemical compounds (University of Turin). The applied principles and technologies will provide new IP opportunities for the partner SMEs in the otherwise crowded kinase inhibitor IP space and will help in the design of new strategies in the discovery of inhibitors for novel kinase targets in the treatment of cancer. The generated compounds will be sold and/or out-licensed to large pharmaceutical companies for continued development. This market is currently undergoing continuous expansion due to large cuts in early drug discovery within most pharmaceutical companies.'

Introduzione (Teaser)

Deregulated kinase activity is implicated in various diseases including cancer, autoimmunity and diabetes. A European initiative is addressing the rapidly growing market for protein kinase inhibitors through a novel technology platform.

Descrizione progetto (Article)

Cells employ various activation mechanisms to transduce signals and control cellular processes. Protein phosphorylation is the most common of these mechanisms and is mediated by protein kinases. More than 500 genes encoding protein kinases have been identified in the human genome and their implication in disease development is rapidly emerging.

Small-molecule kinase inhibitors have been introduced as a new class of drugs, which is expected to produce new and more efficient treatments. With this in mind, the EU-funded ?Translational kinase tumour inhibitor discovery consortium? (TAKTIC) initiative aims to create a new platform for lead compound discovery. To this end, partners are exploiting both in silico and physical compound libraries to identify inhibitory compounds against three protein kinases (IKKa, IKKb and NIK). Researchers will also develop biochemical and cell-based assay systems for assessing the activity of the identified compounds.

Over 2 300 compounds have been screened so far and 72 compounds have been identified that exhibit a 40 % inhibition of target kinase activity.

Based on their effectiveness and required dose, 5 lead compounds have been chosen for further chemical characterisation. Additionally, the three human kinases in question have been cloned, expressed and purified. Ongoing efforts to crystallise these proteins will unveil their three-dimensional structure and aid in the future design of specific inhibitors.

The overall aim of the TAKTIC initiative is to introduce into the European market a new technology platform for drug discovery. The proposed setup will aid pharmaceutical companies to identify new small-molecule inhibitors of protein kinases. The lead candidate compounds are fully patentable and thus offer the potential to ultimately generate fruitful spin-off activities and significant future revenues. This will not only increase the competitiveness of small biotech companies but is envisaged to provide novel treatments for cancer.