Advancing FLIP inhibitors for the treatment of NSCLC

Today, Domainex and Queen’s University Belfast announced that they have secured a late-stage award from the Wellcome Trust Seeding Drug Discovery scheme to advance FLIP inhibitors into clinical evaluation for the treatment of non-small cell lung cancer (NSCLC).

Drug Target Review contacted Trevor Perrior, Research Director at Domainex, to find out more about the cell death regulatory protein FLIP, FLIP inhibitors and Domainex’s collaboration with Queen’s University Belfast.

FLIP is believed to be a key regulator of tumour cell survival that promotes tumour growth and resistance to standard therapies. The Wellcome Trust award will allow the partners to accelerate development of small molecule inhibitors that block FLIP’s pro-survival function. Dr Perrior explained the potential of FLIP inhibition in NSCLC: “FLIP is an anti-apoptotic protein: that is to say, it is involved in switching-off the process of programmed cell death. In many cancers FLIP is overexpressed so that the tumour cells can stop this natural process and achieve abnormal longevity.  By binding to FLIP and preventing its action, our compounds ‘release the brake’ and so the treated cancerous cells enter the death programme, thereby killing the tumour.”

The inhibitors invented by the team have already shown efficacy in preclinical models of NSCLC, as Dr Perrior explained: “Our colleagues at Belfast have shown that our FLIP inhibitors are effective at killing cancer cells and that they prevent tumour growth in models of the disease. Our preclinical studies will extend the breadth of models in which we show a beneficial effect, and will also aim to demonstrate the safety of our compounds, so that we will be ready to take them into clinical trials where we can show their ability to treat cancer patients.”

Domainex and Queen’s University Belfast have been working together to develop the inhibitors. Dr Perrior discussed the origins of that collaboration: “Our collaboration with Queens came about when David Haigh, an ex-colleague of our CEO, was working at Queens and he introduced us to Dan Longley, telling us that Dan had made some exciting discoveries in the FLIP area.  When we met Dan we quickly realised that our Domainex LeadBuilder technology was the ideal way to use his understanding of FLIP biology to start a viable drug discovery project by finding inhibitor compounds.  That was something that was perceived to be tricky, because inhibiting protein-protein interactions like this one has always been regarded as challenging.  But Leadbuilder worked beautifully and we found several hit series, one of which we have now developed into our lead programme.”

But what will the Wellcome Trust funding mean for the development of the small molecule inhibitors? Dr Perrior explained: “We are very grateful for the Wellcome Trust funding, which will allow us to take this project through the remaining stages of the R&D process and into our first human proof of concept clinical trials at Queens University. That’s an expensive process, and without the generous funding from the Trust it would have been difficult for us to secure finance for such a novel approach to cancer treatment, no matter how exciting the long-term prospects might be.”