A year has passed since the start of the TAKTIC project (Translational Kinase Tumour Inhibitor discovery Consortium). A year can be rather short, but it may also be long - all depends on how much you manage to squeeze into it. In my experience, having an EU project to coordinate makes it very long, at least when I look back. On the other hand, when it was time to prepare our first 9-month report, the feeling was that time was running faster and faster, mercilessly eating up the dark December working hours.
At the start of 2013 we were on our way to finishing negotiations with the Commission. Probably the most important part of the negotiation process, which started in October, was the signature of the Consortium Agreement by all partners. Time after time I had to explain to the Technology Transfer Offices of our academic partners the specificity of the program we entered, called "Research for the benefit of SMEs", which demanded that all IP generated within the project had to be kept by the SME partners. Eventually they accepted this and by the end of January the signed agreement could be sent to the Commission. The official start of the project was set to the 1st of February. However, the Grant Agreement (GA) with the EU was signed much later, on 13th of March (the same day the new Pope was elected in the Vatican). Unfortunately this meant that the funds would arrive at best by the end of April, which meant that we had to work for some time using own funds. For some reason we were impatient to start the project, but if I would do this again I would start the project in April.
It was exciting, we were all moving into an unknown territory - we had 3 challenging kinases as targets.
The focus of the project is the NF-κB signalling pathway, which is activated by cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, etc. Disturbances in the regulation of the pathway have been linked to cancer, inflammation and autoimmune diseases, while inhibition of the pathway is implicated in the treatment of these diseases. There are 3 main players within this pathway: (1) A family of dimeric transcription factors called Nuclear Factor κB (NF-κB); (2) inhibitory proteins called inhibitors of NF-κB (IκB); and (3) the IKK kinases (IKKα, IKKβ and NIK). To become active, IKKα and IKKβ need to be phosphorylated on two serine residues (Ser 177 and 181 for IKKβ, and Ser 176 and 180 for IKKα) located in an activation loop, similar to a large number of other kinases. Despite the high sequence similarity between IKKα and IKKβ, the two proteins have distinct functions in NF-κB signalling. While IKKβ is responsible for the activation of the so-called canonical NF-κB pathway used by most stimuli in most cell types, IKKα is involved in the activation of the so-called non-canonical or alternative NF-κB pathway. All of the non-canonical NF-κB inducers identified so far are known to signal through NIK, a MAP kinase kinase kinase (MAP3K) member responsible for the phosphorylation of IKKα homodimers. Targeting of the canonical and non-canonical signalling pathways with IKKβ and IKKα/NIK inhibitors, respectively, is considered to be a potential strategy for the treatment of NF-kB associated diseases (see for example the NF-κB inhibitors site).
Apart from SARomics Biostructures, the project includes ProQinase, Prestwick Chemical, the Israel Structural Proteomics Centre at the Weizmann Institute of Science, two groups from the University of Turin – the Depts. of Science and Drug Technology and Medicine and Experimental Oncology, and finally the TechMedILL platform at the University of Strasbourg). I should say that all partners made a brilliant contribution during these first months, to the extent that when we met in June in Lund at our first project review meeting, we already had real results to discuss! The first library screens had already resulted in some hits, the chemistry program and compound modifications were starting to reveal new results (some of them quite unexpected and will be published in the near future!), proteins were produced and delivered for biochemical activity assays and the cell-based assay program was in place and running! The next bunch of results came already after the summer - the compounds, which were identified in the in silico screen against one of the targets, were either purchased or synthesized and their biochemical and cell-based tests started. When our second project review meeting took place in Strasbourg at Prestwick Chemical at the end of October, we already had nice hits for two of the targets. Based on the results, it was eventually decided to focus the work on NIK kinase. This step was part of the project plan, which takes into account the rather short project period we have (two years).
We are now looking forward for the optimization of the identified compounds, crystallization of NIK in complex with these compounds, and of course nano-molar NIK inhibitors!
In the photo below is the TAKTIC consortium meting in Turin, 13/03/2014 - one year after the start of the project!