AKT kinases as therapeutic targets

Abstract

AKT, or protein kinase B, is a central node of the PI3K signaling pathway that is pivotal for a range of normal cellular physiologies that also underlie several pathological conditions, including inflammatory and autoimmune diseases, overgrowth syndromes, and neoplastic transformation. These pathologies, notably cancer, arise if either the activity of AKT or its positive or negative upstream or downstream regulators or effectors goes unchecked, superimposed on by its intersection with a slew of other pathways. Targeting the PI3K/AKT pathway is, therefore, a prudent countermeasure. AKT inhibitors have been tested in many clinical trials, primarily in combination with other drugs. While some have recently garnered attention for their favorable profile, concern over resistance and off-target effects have continued to hinder their widespread adoption in the clinic, mandating a discussion on alternative modes of targeting. In this review, we discuss isoform-centric targeting that may be more effective and less toxic than traditional pan-AKT inhibitors and its significance for disease prevention and treatment, including immunotherapy. We also touch on the emerging mutant- or allele-selective covalent allosteric AKT inhibitors (CAAIs), as well as indirect, novel AKT-targeting approaches, and end with a briefing on the ongoing quest for more reliable biomarkers predicting sensitivity and response to AKT inhibitors, and their current state of affairs.

Keywords: AKT kinases; Cancer; Inflammation; Overgrowth syndromes; Therapy.

Fig. 1

A Schematic of AKT activation and inactivation; activating and inactivating steps are indicated by arrows and blunt-ended lines, respectively (modified from [130]). B AKT substrates; functional and biological consequences of their phosphorylation. Schematic showing the cellular functions of known AKT substrates. Direct phosphorylation by AKT is indicated by continuous lines, leading to activation (arrow end) or inhibition (blunt end). See main text for details

Fig. 2

Modular network of crosstalk among AKT and other signaling pathways. Lines with arrow end and blunt end denote functional activation or inhibition, respectively

Fig. 3

Structure of the complex of human AKT1 with capivasertib (PDB entry 4GV1). A Schematic of the complex of AKT1 (gold) with capivasertib (purple); phosphorylated Thr308 on activation loop is shown in sticks. B Close-up of AKT1 interacting residues that are within 4 Å of capivasertib. Dotted lines indicate hydrogen bonds