The Akt kinases are critical regulators of cell physiology, but have also been associated with the development of thrombosis, cancer and other major killer diseases. This kinase family is composed of three highly homologous isoforms (with 73% sequence similarity): Akt1, Akt2 and Akt3. Gene knockout studies have shown that Akt isoforms have non-overlapping regulatory functions in cell which contribute to their pathological and physiological diversity in vivo. For example, both Akt2 and Akt3 regulate platelet activation in thrombosis, whereas in vivo models deficient in these proteins develop a severe defect in haemostatic plug formation. This observation together with the well-established Akt-isoform signalling in cancer underscore the urgent need of Akt-isoform-specific inhibitors for next-generation precision medicines.
Recently, the revolutionary approaches in drug development termed PROTAC (PROteolysis-TArgeting Chimera) have attracted considerable attention in repurposing broad-spectrum therapeutics to be target-selective degraders. PROTACs are bifunctional molecules capable of binding to a ubiquitinase complex and the protein target simultaneously, thereby promoting selective target degradation. Importantly, rational design of PROTAC constructs has led to isoform-specific degraders to target oncogenic kinases and transcription factors otherwise intractable to functional inhibition.
This project aims to develop Akt-isoform-specific PROTACs and to investigate their therapeutic potential in thrombosis. The specific objectives of the project include: (i) rational design and chemical synthesis of Akt-isoform-specific PROTACs; (ii) phenotypic validation of PROTAC efficacy and selectivity in cancer cells and platelets; and (iii) investigating the spectrum of targeting of PROTACs using modern chemoproteomic technologies to understand Akt isoform function in cancer cells and platelets with a view to developing new therapeutics.