COILED (Center for Open Innovation in LEad Discovery) announced today the first results of an ultra High Throughput Screening (uHTS) campaign on a prime epigenetic enzyme target that plays a key role in controlling trained immunity. After screening a collection of 300,000 compounds, hit confirmation resulted in 6 classes of known and novel scaffolds. A hit-to-lead program, currently involving biophysical and computational analysis of target engagement along with Structure-Activity Relationship (SAR) profiling has been initiated for three novel classes of scaffolds. Modulation of trained immunity by interfering with specific histone modifying enzymes not only opens-up a new avenue for the design of novel therapeutic strategies to treat immune deficiency states as in sepsis and cancer, but also has a huge potential for treating hyperinflammatory disorders such as atherosclerosis and rheumatoid arthritis.
The joint effort of project partners at Radboud University, Inntrest Consultancy and BioAxis Research with organic synthesis, medicinal chemistry and computational chemistry activities along with activities at Pivot Park Screening Centre in assay development, miniaturization, uHTS and Hit-to-Lead biological profiling has been the cornerstone of this early phase success. Professor Mihai Netea at Radboudumc, who discovered trained immunity, will further contribute to this success by participating in the hit-to-lead and lead optimization phases.
“It is great to announce these very promising first results,” tells Steven van Helden, Chief Technology Officer at Pivot Park Screening Centre. “By combining the project partner’s individual expertise and infrastructure we’ve been able to take very promising first steps towards developing therapies for diseases governed by trained immunity. Using our state-of-the-art infrastructure and in-depth experience in screening and medicinal chemistry, we discovered three novel classes of scaffolds, and de-risked the entire hit-to-lead process by eliminating structurally unfavorable compounds.
“These results are a tremendous impetus to the COILED trained immunity program” according to Jac Wijkmans, COILED program lead & founder Inntrest Consultancy. “Medicinal chemistry-driven hit-to-lead optimization of the novel drug-like scaffolds will provide an important addition to our ongoing lead discovery activities. Together with the group of Professor Floris Rutjes of the Radboud University we are now making great strides in identifying potent leads for in vivo testing and further validating the clinical importance of trained immunity.”
The trained immunity project is now gaining further momentum with accelerating assay development activities for another target, relevant to trained immunity in order to carry out the second uHTS campaign during 2018. Follow up activities for the second screen will be initiated in late 2018/early 2019.
About COILED: COILED (Center for Open Innovation in Lead Discovery) is a collaborative drug discovery initiative. COILED amalgamates leading academic biomedical research with industry-standard medicinal chemistry to accelerate and valorize innovation. Radboud University, Radboudumc, Inntrest Consultancy, Pivot Park Screening Centre, BioAxis Research and Pansynt have built a unique drug discovery program to deliver the next generation of immuno-modulatory drugs to combat disease with an unmet medical need.
About Trained Immunity: Immune responses are classically divided into innate immune responses, which react rapidly and nonspecifically upon encountering a pathogen, and adaptive immune responses, which are slower to develop but are specific and build up immunological memory. However, the dogma that only adaptive immunity can build immunological memory has been challenged by Netea and co-workers who showed that innate immune cells can display adaptive characteristics after challenge with pathogens or their products. This de facto immunological memory has been termed ‘trained immunity’ or ‘innate immune memory’. Read further on the COILED website: www.coiled.nl.
Contact: For more information about this press release contact COILED by e-mail (firstname.lastname@example.org) or phone (+31 (0)6 24 39 84 84).