Periodic Reporting for period 2 - TASPPI (Targeted small-molecule Stabilisation of Protein-Protein Interactions)
Période du rapport: 2018-02-01 au 2020-01-31
"The goal of TASPPI is the development and use of small molecules that work as 'molecular glues' between the contact surfaces of regulatory protein complexes. These molecules have the potential to be developed into an entirely new class of therapeutic agents. Most drugs that are currently developed are based on inhibitors of proteins like enzymes (fro example kinases and proteases). However, in many physiological instances, stabilization of regulatory complexes could create a therapeutic benefit in many diseases. Importantly, this strategy has been validated by the fact that a number of natural products - among them the immunosuppressants rapamycin and FK506 or the anti-cancer agent taxol - mediate their physiological effect by stabilizing specific protein-protein interactions (PPIs). We are working on PPIs of the 14-3-3 protein class. These adapter proteins are so-called hub proteins that interact with several hundred other proteins in human cells. Among their interactions partners are many human-disease related proteins like Tau (Alzheimer's disease), LRKK2 (Parkinson""s disease), p53, C-Raf, c-Myc (cancer), IRS, Foxo1 (diabetes), CFTR (cystic fibrosis), and NFkappaB (inflammation), for example.
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 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 the first year of TASPPI mainly the basis of the identification and characterization of a number of 14-3-3 PPI project was laid. This includes the establishment of assays for measuring the binding of 14-3-3 to its partner proteins as well as the respective co-crystal structures of the 14-3-3 protein complexes. In addition to in-vitro assays, also some cellular systems were prepared to analyze the physiological potency of the compounds in development. Among these assay are subcellular localization systems for for example nuclear receptors and transcription factors.
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.
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.
In this project we will develop a new class of drug development candidates for novel therapeutic approaches for a number of diseases like Alzheimer's, cancer, and inflammation. Stabilizing regulatory protein complexes will significantly increase our possibilities for pharmacological intervention in yet not successfully treatable diseases.
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.
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.