Periodic Reporting for period 2 - TASPPI (Targeted small-molecule Stabilisation of Protein-Protein Interactions)
Reporting period: 2018-02-01 to 2020-01-31
In all the aformentioned cases, stabilization of 14-3-3 binding to these proteins would convey a positive effect on disease progression and could be used clinically. Also in the case of 14-3-3 PPIs, a class of natural products is known that stabilize the binding of 14-3-3s to its partner proteins. These so-called fusicoccanes have already been shown to display a physiological effect by enhancing the binding of 14-3-3 proteins to C-Raf and CFTR. Detailed structural biology and biophysics studies revealed how these natural products stabilize the 14-3-3/partner protein complexes. In the course of these studies it could be shown that fusicoccanes bind to well-defined protein interface pockets and working like a glue between the proteins. This 'natural-product validation' of the 14-3-3 PPI stabilization concept is the starting point for our projects to also identify more chemically tractable starting points for drug discovery.
In the ITN TASPPI we have not only identified very promising drug discovery starting point for making the 14-3-3 interactome accessible for the development of new medicines, but also trained a group of highly qualified researchers that are ideally equipped for conquering the challenges of modern drug discovery. In addition, a collaboration network between academic institutions and pharma- as well as biotech companies was established that will continue to work together to bring new potential solutions to some of the most urgent medical demands of our current and future society"
In total 4 different screening assays, plus 7 biophysical characterization assays were developed, several compound liraries were screened and 123 co-crystal structures were solved. The first screening hits are available and currently confirmed by a number of methods, including cellular assays.
A number of training modules, training events and summer schools have been organized for the young researchers working in TASPPI. In addition, 15 publications have been accepted and many more are in preparation.
In March 2020 a biotech startup as a spin-out of the Eindhoven University of Technology was founded which will continue to work on some of the projects of this ITN. In addition, a new ITN consortium was formed with partners from TASPPI and beyond. This consortium has submitted proposal in January 2020.
We expect that based on results of TASPPI a new approach for the development of therapeutic agents will be established. Both a venture-backed start-up and intensified collaboration with Pharma will be instrumental to achieve this goal that will have significant implications for patients as well a for the creation of commercial value in the EU.