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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.

SUBMITTER: Nitulescu GM

PROVIDER: S-EPMC4750533 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Nitulescu George Mihai GM Margina Denisa D Juzenas Petras P Peng Qian Q Olaru Octavian Tudorel OT Saloustros Emmanouil E Fenga Concettina C Spandidos Demetrios Α DΑ Libra Massimo M Tsatsakis Aristidis M AM

International journal of oncology 20151224 3

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, prolif ...[more]

PMID: 26698230

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Project description:Thirty-six percent of US adults are obese, and many cannot lose sufficient weight to improve health with lifestyle interventions alone.To conduct a systematic review of medications currently approved in the United States for obesity treatment in adults. We also discuss off-label use of medications studied for obesity and provide considerations for obesity medication use in clinical practice.A PubMed search from inception through September 2013 was performed to find meta-analyses, systematic reviews, and randomized, placebo-controlled trials for currently approved obesity medications lasting at least 1 year that had a primary or secondary outcome of body weight change, included at least 50 participants per group, reported at least 50% retention, and reported results on an intention-to-treat basis. Studies of medications approved for other purposes but tested for obesity treatment were also reviewed.Obesity medications approved for long-term use, when prescribed with lifestyle interventions, produce additional weight loss relative to placebo ranging from approximately 3% of initial weight for orlistat and lorcaserin to 9% for top-dose (15/92 mg) phentermine plus topiramate-extended release at 1 year. The proportion of patients achieving clinically meaningful (at least 5%) weight loss ranges from 37% to 47% for lorcaserin, 35% to 73% for orlistat, and 67% to 70% for top-dose phentermine plus topiramate-extended release. All 3 medications produce greater improvements in many cardiometabolic risk factors than placebo, but no obesity medication has been shown to reduce cardiovascular morbidity or mortality. Most prescriptions are for noradrenergic medications, despite their approval only for short-term use and limited data for their long-term safety and efficacy.Medications approved for long-term obesity treatment, when used as an adjunct to lifestyle intervention, lead to greater mean weight loss and an increased likelihood of achieving clinically meaningful 1-year weight loss relative to placebo. By discontinuing medication in patients who do not respond with weight loss of at least 5%, clinicians can decrease their patients' exposure to the risks and costs of drug treatment when there is little prospect of long-term benefit.

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

Publications

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

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