MapInDegraders · Closing the gap: studying non-obvious ligand induced degradation events
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-04-01 → 2023-03-31
- EU contribution
- €174,167
- Participants
- 1
- Scheme
- MSCA-IF
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Results in brief
Closing the gap: studying non-obvious ligand induced degradation events
Cancer remains a challenging disease with an urgent need for new therapeutic strategies. One emerging new pharmacology aiming to address this demand is termed targeted protein degradation. Instead of inhibiting the disease-causing protein, the drugs of this class lead to its removal. Despite this strategy coming with multiple advantages, the design of so-called degrader molecules has been challenging. On the one side, the implementation of PROTACs, or proteolysis targeting chimeras, suffers from large unfavorable molecular weights, leading to suboptimal pharmacological properties such as cell penetration. On the other side, smaller degrader molecules do exist, e.g. molecular glue degraders, but their discovery has often been quite serendipitous. We hypothesized that an untapped resource may be hidden in the already developed molecules that fall under this inhibitory-centric paradigm. Indeed, for these inhibitors sporadic reports already exemplified that these can lead to target (here the disease causing protein) destabilization. A quantitative and qualitative understanding of these processes is, however, largely lacking and hampers any translation efforts. In this project we thus explored these non-obvious inhibitor-induced protein destabilization events for one major drug target class: the protein kinases. This work thus aids closing the gap of our understanding how small molecules which were initially designed to inhibit a protein can also lead to their degradation. This may thus provide an alternative route to engineer degrader molecules and could pave the way towards novel, alternative therapeutic strategies in the battle against cancer.
Data: CORDIS, © European Union
Project objective
Inhibitor-induced target destabilisation has been reported sporadically in recent years. Importantly, despite never actually having been put in place on purpose – or by design – these effects often play a significant role towards their therapeutic effect. To date, no systematic approach to map or quantify these serendipitous destabilising events has, however, been performed, representing a huge underexplored space with large translational potential. I here propose to study ligand-induced destabilisation by utilising the plethora of available protein kinase inhibitors to systematically map their kinase degrading abilities. First, an innovative in vivo assay will be developed to monitor kinase stability at scale. Next a protein kinase inhibitor library will be screened and inhibitor-destabilised kinase pairs will be identified using automated high-throughput microscopy, coupled to fluorescent activated cell sorting and next generation sequencing. Pharmacokinetic mode-of-action binning and machine-learning based computational data mining will chart the map of ligand-induced destabilisation and delineate crucial protein, chemical and/or biophysical properties. Finally, based on the principal mode-of-action identification, measured effect size and translational potential, in-depth mechanism of action studies will be conducted for one selected inhibitor-kinase pair. To that end, a multi-omics approach consisting of genome-wide CRISPR screens and orthogonal genomics and proteomics strategies will be conducted. The project will delineate the underlying concepts of ligand-induced destabilisation using protein kinase inhibitors as a chemically well explored compound space and thus open new avenues to tap into the translationally intriguing area of designing targeted protein degraders for future medical applications.
Original text from CORDIS.
Participants
- CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH · WienCoordinatorAustria
Links
Data: CORDIS, © European Union