Novel First-In-Class FLIP Inhibitors for the Treatment of Cancer

Queen’s University Belfast and Domainex are pleased to announce that their joint project team has successfully identified novel first-in-class small molecule inhibitors of the anti-apoptotic protein FLIP. The team has generated data suggesting multiple therapeutic opportunities for a FLIP inhibitor in both the single agent and combination settings and is now seeking a commercial partner for further development of the novel inhibitors.

The team is presenting the FLIP inhibitor programme at the AACR annual meeting in Atlanta on 31 March 2019 (New Molecular Targets poster session, poster 382 /14). The poster showcases the on-target effects of the inhibitors, their drug-like properties, their potency against B Cell Lymphomas, triple negative breast cancer and KRAS and EGFR mutant non-small cell lung cancer, and their potential for combination with chemotherapy, immune oncology agents and EGFR-targeted therapeutics.

The next phase of the programme will comprise selection of a pre-clinical development candidate and completion of pre-clinical activities. Profs Dan Longley (Biology lead) and Tim Harrison (Med Chem lead) are attending the AACR meeting and will be actively engaging in discussions with potential partners at the meeting.

This FLIP programme has been funded by the Wellcome Trust and has focussed on the identification and optimisation of novel first-in-class small molecule FLIP-FADD protein-protein interaction inhibitors. FLIP is a non-redundant inhibitor of Caspase 8 and functional FLIP allows tumour cells to evade cell death and promotes tumour growth and therapy resistance. The novel FLIP inhibitors activate Caspase 8 and have shown efficacy in a number of pre-clinical models including clinically challenging KRAS and EGFR mutant non-small cell lung cancer.

Trevor Perrior, Chief Executive Officer of Domainex, commented: "Our medicinal chemists have been delighted to work on this exciting target and enable Prof. Dan Longley and his team to identify and optimise the FLIP inhibitors. There were several challenges that we had to solve in order to identify hits and develop a series of potential drug compounds that are potent and selective. We look forward to at least one of these compounds progressing towards the clinic for the benefit of patients. The funding secured from the Wellcome Trust is a clear endorsement of the strength of the integrated drug discovery platform of Domainex to deliver molecules with disease-modifying potential and we remain deeply committed to supporting academic translational research."

Prof. Dan Longley from the Centre for Cancer Research and Cell Biology (CCRCB) at Queen’s University Belfast, added: "Resistance to cancer therapeutics such as chemotherapy is a major clinical problem that limits the effectiveness of many current cancer treatments. Very often, this is caused by the failure of anti-cancer therapies to kill the cancer cells. FLIP is a cellular protein that cancer cells frequently express at high levels, and this increases their resistance to chemotherapy and other types of therapy used to treat cancer, such as radiotherapy. The agents that we are developing target FLIP and prevent it from causing therapy resistance. In addition, some tumour-promoting immune cells also need FLIP, so our FLIP inhibitors may also have beneficial effects in the tumour microenvironment by reactivating immune cells to attack cancer cells."

About Cancer Research at Queen’s University Belfast
The Centre for Cancer Research and Cell Biology (CCRCB) was developed with the explicit aim of translating basic scientific programmes into the clinical arena and is a dynamic research Centre within the School of Medicine, Dentistry and Biomedical Sciences in Queen’s University Belfast. Adjacent to the Northern Ireland Clinical Cancer Centre on the Belfast City Hospital campus, CCRCB is the first Comprehensive Cancer Centre in Ireland and is one of 15 Cancer Research UK (CRUK) designated Centres of Excellence in the UK. The Centre was also awarded Experimental Cancer Medicine Centre (ECMC) status, one of 18 such UK Centres.

About Domainex
Domainex was established in 2001 as a spin-out from University College London, Birkbeck College and the Institute of Cancer Research. Domainex is a privately-owned company that provides integrated drug discovery research services to global pharmaceutical, biotechnology and academic partners. Its services cover a wide range of the drug research process, from disease target selection to pre-clinical candidate nomination. Domainex's services include recombinant protein expression and use of its proprietary technology platform, Combinatorial Domain Hunting to identify soluble protein fragments for structural biology and assay development. Hit finding activities encompass assay development and screening utilising its BioassayBuilder, FragmentBuilder and LeadBuilder platforms. The core of the service offering is undertaking multi-parameter medicinal chemistry optimisation of hits and leads with its ‘every compound counts’ approach, which can save up to 30% on the average industry time from target to candidate.

About the Wellcome Trust
Wellcome exists to improve health by helping great ideas to thrive. We support researchers, we take on big health challenges, we campaign for better science, and we help everyone get involved with science and health research. We are a politically and financially independent foundation.

About The Queen’s University of Belfast
The Queens University of Belfast (Queen’s) is a prestigious UK Russell Group affiliated university, Queen's is ranked among the top 180 universities worldwide. Queen’s is consistently in the top 10 universities in the UK for research impact when measured by HEBCI based on IP-related Revenue (consisting of revenue from IP licences and divestment in spin out companies). In the past 4 years (through to the year ending July 2018) Queen’s has generated significant levels of impact when measured based on fundamental innovation and commercialisation indicators. These include: ~£61.4 million in IP related revenue in the past 4 years; 273 new invention disclosures (60% of which are in the life science faculty); 58 new priority patent applications (65% of which are in the life science faculty); 75 new royalty-bearing Licence, Options or Agreements (70% of which are in the life science faculty). The FLIP project has been led by Prof. Daniel Longley and Prof. Tim Harrison based at the Centre for Cell Biology and Cancer Research (CCRCB) at Queen’s. Researchers at CCRCB are finding new ways to advance and tackle cancer care by taking the lead in cancer research, improving patient outcomes, training the next generation of scientists/clinicians, and enhancing the competitiveness of the UK life sciences sector.

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