Queen’s University Belfast and Domainex identify novel first-in-class FLIP inhibitors

Mar 29 2019

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 optimization 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 tumor cells to evade cell death and promotes tumor 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.

To arrange to meet the team at AACR please contact Enda Gribbon: ([email protected])

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 optimize 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 tumor-promoting immune cells also need FLIP, so our FLIP inhibitors may also have beneficial effects in the tumor microenvironment by reactivating immune cells to attack cancer cells.”