Structural requirements of isoform-specific inhibitors of Akt: Implications in the development of effective cancer treatment strategies

Abstract

Akt, also known as protein kinase-B, is an important therapeutic target in the treatment of cancer due to its pivotal roles in the signaling pathways that regulate various hall-mark features of cancer cells such as cell growth, survival, migration, differentiation, and metabolism. The three closely related isoforms of Akt viz., Akt1, Akt2, and Akt3 exhibit distinct physiological roles that affect cellular behavior and tumor development, making isoform selectivity a crucial driving factor in the design and development of inhibitors. This review outlines key amino acids and their structural traits in Akt isoforms, potentially dictating isoform selectivity. We present an analysis of existing structure-activity relationship data of covalent-allosteric Akt inhibitors to shed light on isoform selectivity. Additionally, a brief review of potential predictive biomarkers in enhancing the therapeutic efficacy of Akt inhibitors is presented. Identifying biomarkers that can reliably predict patient response to treatment is crucial for personalizing cancer therapies and improving overall treatment outcomes. By integrating predictive biomarker identification with the ongoing development of isoform-selective Akt inhibitors, it is plausible to establish a foundation for more precise and efficacious interventions in cancer therapy.