New research into new small molecule IKKα inhibitors

Dr Elaine Willmore – University of Newcastle, Newcastle, UK

I’d just like to tell you a little about the research that we’ve been doing recently. In contrast to a lot of the data that has been presented here which is on clinical trials and outcomes of trials, we’ve been looking at very early stage drug discovery to try and identify new kinase inhibitors that would be effective in CLL and probably in other B-cell malignancies as well. We’ve been looking at the NF-kappa B pathway; NF-kappa B is a transcription factor which is very important in biology for inflammatory response but it happens to be very important in B-cells as well and in CLL cells. The reason that we started looking at NF-kappa B was because there’s a lot of data from our collaborator, Dr Chris Pepper, showing that in CLL cells NF-kappa B is very highly expressed. Therefore he proposed that it would be a good target for drug discovery.

Following on from his work which looked at a particular signalling pathway of NF-kappa B which was the classical or canonical pathway, we wanted to try and discover whether the non-canonical NF-kappa B signalling pathway was also important because there is a lot of data in the literature showing that in lymphoma and other B-cell diseases that actually it was non-canonical signalling that was important and it hadn’t really been widely studied. Around the same time we developed a very exciting collaboration with Professor Simon Mackay’s group at the University of Strathclyde in Glasgow. He was able to provide us with some of his very potent and selective small molecule inhibitors of a particular kinase which is involved in B-cell receptor signalling, IKKα.

So we started a project about two years ago investigating these kinases in CLL cells that we were collecting from patients and trying to understand whether the inhibitors would affect the viability or growth of the cells. Very quickly we discovered that not only were the compounds very effective but they were also inducing apoptosis in CLL cells. So this encouraged us that this could be an important target in CLL. We were then able to get some more funding, a Pump Priming Grant from the MRC Confidence in Concept scheme which allowed us to employ someone for six months and really work hard to get some pilot data together and validate our earlier findings. That’s really what I’ve presented today at the meeting. So we’ve shown that not only do these inhibitors, these more recent inhibitors, inhibit CLL cell proliferation and signalling but in a model that we’ve used that mimics the actual in vivo microenvironment we’ve been able to show that these inhibitors really do stop the cells proliferating.

What we want to do next is obviously gain some more funding to extend our studies and really understand how these inhibitors are working, especially if these inhibitors will work more effectively on CLL tumour malignant cells and not hit normal B-cells. So we need to get an understanding of the therapeutic index. We also need to understand, because NF-kappa B that we’re targeting is a transcription factor, we really need to understand which genes are being affected – are they downregulated, are they upregulated and which genes are leading to the altered survival that we see of these CLL cells.

So that’s a quick summary of our research and the work that we’ve presented today.