In search of novel molecular drugs
Protein kinases constitute enzymes that phosphorylate and thus activate other proteins. Protein phosphorylation is among the most common mechanisms employed in signal transduction and the control of various cellular processes. Approximately 30 % of all human proteins may be phosphorylated by kinases and their deficiency has detrimental consequences leading to cancer, autoimmunity and central nervous system disorders. Small-molecule kinase inhibitors have therefore emerged as a new class of efficient treatments against these diseases. The EU-funded TAKTIC (Translational kinase tumour inhibitor discovery consortium) project focused on inhibitors of the IkB kinase complexes (IKKa, IKKb) and NIK kinases implicated in the NF-kB signalling pathway. In the absence of a signal, the IkB inhibitors bind to the NF-kB transcription factors and sequester them in the cytoplasm. The NF-kB cascade commences with upstream signals from the surface or inside the cell that activate the IKK complex to phosphorylate IkB, and enable NF-kB to enter the nucleus and regulate gene expression. TAKTIC researchers screened over 2 300 compounds for the identification of highly specific inhibitory molecules against kinases of the NF-kB pathway. The process was supported by in silico modelling and docking studies. Based on kinase selectivity and inhibition potency, the hits were clustered into 15 different chemical series and optimised based on structure-activity relationships (SAR). Promising lead compounds were discovered against NIK and IKK kinases with potency at the nanomolar range. Overall, TAKTIC activities are expected to increase the competitiveness of the implicated biotech companies and provide novel treatments for many diseases including cancer. The generated platform for drug discovery has the potential to aid pharmaceutical companies in the identification of new small-molecule inhibitors against other protein kinases.
