Expanding The Scope of AKT Modulation Through Targeted Protein Degradation

Abstract

AKT is a critical mediator of the phosphoinositide 3-kinase (PI3K) signalling cascade, playing a key role in regulating essential cellular processes. The identification of AKT as one of the most dysregulated pathways in cancer led to the development of multiple classes of inhibitors. Despite numerous inhibitors entering clinical investigation and leading to the FDA approval of Capivasertib, an ATP-competitive AKT inhibitor, in November 2023, AKT modulation through inhibition was characterised by toxicity and poor clinical efficacy. Targeted Protein Degradation (TPD) spearheaded by PROTACs boasted a paradigmatic shift in drug discovery and was demonstrated to be a valid therapeutic alternative to modulate AKT. To date, numerous AKT-targeting PROTACs have been disclosed. The majority of them outperformed the inhibitors in suppressing AKT activity, nurturing higher potency and improved selectivity. Notably, enhanced antiproliferative effects, sustained by more robust and prolonged inactivation of the AKT downstream signalling was observed. This review highlights AKT as a central therapeutic target in oncology and focuses on AKT modulation through a targeted protein degradation approach mainly using PROTACs. The review aims at illustrating all the AKT-targeting PROTACs disclosed in literature to date, a powerful new pharmacological tool that might remarkably expand the scope of AKT-targeted therapies and further elucidate the role of AKT in both normal and cancer-related phenotypes.