High Throughput Synthesis of PROTACs to target tyrosine kinases in human platelets.

The key objective of this research is to conduct efficient synthesis of proteolysis targeting chimeras (PROTACs) for the targeted degradation of kinases in human platelets.

Proteolysis-targeted chimeras (PROTACs) are a rapidly developing modality within drug discovery which utilise endogenous proteasomal degradation pathways to target proteins of medicinal interest. The synthesis of PROTACs can be conducted in a modular fashion, which involves linking a protein of interest (POI) warhead and an E3-ligase ligand. This project looks to develop the high-throughput synthesis of PROTACs through variation of the linker and E3-ligase ligands for the rapid exploration of PROTAC chemical space. Development of a modular high-throughput synthetic workflow will increase the chances of finding potent PROTACs.

Use of PROTACs to target proteins in platelets is less explored but is a promising target for anti-thrombotic therapies as platelets express E3-ligases and are heavily involved in clotting. Parallel synthesis and appropriate biological assays will be used to assess the efficacy of PROTACs in platelets.