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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.

Protein kinase B (Akt), similar to many other protein kinases, is at the crossroads of cell death and survival, playing a pivotal role in multiple interconnected cell signaling mechanisms implicated in cell metabolism, growth and division, apoptosis suppression and angiogenesis. Akt protein kinase displays important metabolic effects, among which are glucose uptake in muscle and fat cells or the suppression of neuronal cell death. Disruptions in the Akt-regulated pathways are associated with cancer, diabetes, cardiovascular and neurological diseases. The regulation of the Akt signaling pathway renders Akt a valuable therapeutic target. The discovery process of Akt inhibitors using various strategies has led to the identification of inhibitors with great selectivity, low side-effects and toxicity. The usefulness of Akt emerges beyond cancer therapy and extends to other major diseases, such as diabetes, heart diseases, or neurodegeneration. This review presents key features of Akt structure and functions, and presents the progress of Akt inhibitors in regards to drug development, and their preclinical and clinical activity in regards to therapeutic efficacy and safety for patients.

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Monosodium glutamate (MSG) is an umami substance widely used as flavor enhancer. Although it is generally recognized as being safe by food safety regulatory agencies, several studies have questioned its long‐term safety. The purpose of this review was to survey the available literature on preclinical studies and clinical trials regarding the alleged adverse effects of MSG. Here, we aim to provide a comprehensive overview of the reported possible risks that may potentially arise following chronic exposure. Preclinical studies have associated MSG administration with cardiotoxicity, hepatotoxicity, neurotoxicity, low‐grade inflammation, metabolic disarray, and premalignant alterations, along with behavioral changes. However, in reviewing the available literature, we detected several methodological flaws, which led us to conclude that these studies have limited relevance for extrapolation to dietary human intake of MSG risk exposure. Clinical trials have focused mainly on MSG effects on food intake and energy expenditure. Besides its well‐known impact on food palatability, MSG enhances salivary secretion and interferes with carbohydrate metabolism, while the impact on satiety and post‐meal recovery of hunger varied in relation to meal composition. Reports on MSG hypersensitivity or links of its use to increased pain sensitivity and atopic dermatitis were found to have little supporting evidence. Many of the reported negative health effects of MSG have little relevance for chronic human exposure and are poorly informative as they are based on excessive dosing that does not meet with levels normally consumed in food products. We conclude that further clinical and epidemiological studies are needed, with an appropriate design, accounting for both added and naturally occurring dietary MSG.