Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review)

Abstract

Targeted cancer therapies are used to inhibit the growth, progression, and metastasis of the tumor by interfering with specific molecular targets and are currently the focus of anticancer drug development. Protein kinase B, also known as Akt, plays a central role in many types of cancer and has been validated as a therapeutic target nearly two decades ago. This review summarizes the intracellular functions of Akt as a pivotal point of converging signaling pathways involved in cell growth, proliferation, apoptotis and neo-angiogenesis, and focuses on the drug design strategies to develop potent anticancer agents targeting Akt. The discovery process of Akt inhibitors has evolved from adenosine triphosphate (ATP)-competitive agents to alternative approaches employing allosteric sites in order to overcome the high degree of structural similarity between Akt isoforms in the catalytic domain, and considerable structural analogy to the AGC kinase family. This process has led to the discovery of inhibitors with greater specificity, reduced side-effects and lower toxicity. A second generation of Akt has inhibitors emerged by incorporating a chemically reactive Michael acceptor template to target the nucleophile cysteines in the catalytic activation loop. The review outlines the development of several promising drug candidates emphasizing the importance of each chemical scaffold. We explore the pipeline of Akt inhibitors and their preclinical and clinical examination status, presenting the potential clinical application of these agents as a monotherapy or in combination with ionizing radiation, other targeted therapies, or chemotherapy.

The T-Box transcription factor 3 in development and cancer

“…These highly homologous isoforms phosphorylate a plethora of substrates that are involved in the regulation of key cellular processes including cell proliferation, apoptosis, and migration (94). It is well established that constitutive activation of Akt, through PI3K amplification or PTEN mutation, contributes to the oncogenic process and is associated with a poor prognosis and resistance to chemo-and radio-therapy (94). Indeed, Akt activation is one of the most frequent molecular alterations in cancers, including melanoma, gastric, pancreatic, breast, sarcoma and prostate cancer (95)(96)(97)(98).…”

ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease

“…Most AKT inhibitors, including ARQ 092, are being developed as anti-cancer drugs. 25 Given the fact that some cancer patients are at high risk of thrombogenesis, 37 our results also provide indirect evidence that ARQ 092 may be an effective drug in cancer patients with thrombotic complications.…”

“…24,25 ARQ 092 has been reported to be an orallyavailable, highly-selective AKT inhibitor. 26,27 Recent studies show that ARQ 092 blocks the activity of AKT1, AKT2, and AKT3 with IC 50 values of 5.0, 4.5, and 16 nM, respectively, and has excellent selectivity (>1,000-fold) over other kinases.…”

Phosphorylation-Dependent Inhibition of Akt1

“…This need is reflected in clinical trials which show that non-specific Akt inhibition in cancer therapy, due to inadvertent off-targeting of closely related kinases or multiple Akt isozymes, can result in detrimental side-effects including liver damage and metabolic disorders [37][38][39][40]. Accordingly, the development of small molecule inhibitors for Akt has reflected this sentiment towards engineering greater target specificity [28]. From the earliest ATP-competitive inhibitors that unintentionally inhibited related AGC kinases, to more recent allosteric inhibitors that preferentially target Akt or even a subset of Akt isozymes, the continued pursuit for Akt1 inhibitor specificity requires an expanded understanding of the molecular basis of Akt1 activation and inhibition.…”

“…Several classes of chemical inhibitors were developed to repress aberrant Akt1 activity in cancer cells [28]. Early Akt1 inhibitors focused on ATP competitive compounds [29], yet these molecules suffered from significant cross reactivity with other AGC family kinases [30].…”