title: 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.
authors.affiliation: Faculty of Pharmacy, 'Carol Davila' University of Medicine and Pharmacy, Bucharest 020956, Romania.
authors.forename: George Mihai
authors.initials: GM
authors.lastname: Nitulescu
authors.affiliation: Faculty of Pharmacy, 'Carol Davila' University of Medicine and Pharmacy, Bucharest 020956, Romania.
authors.forename: Denisa
authors.initials: D
authors.lastname: Margina
authors.affiliation: Department of Pathology, Radiumhospitalet, Oslo University Hospital, 0379 Oslo, Norway.
authors.forename: Petras
authors.initials: P
authors.lastname: Juzenas
authors.affiliation: Department of Pathology, Radiumhospitalet, Oslo University Hospital, 0379 Oslo, Norway.
authors.forename: Qian
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Faculty of Pharmacy, 'Carol Davila' University of Medicine and Pharmacy, Bucharest 020956, Romania.
authors.forename: Octavian Tudorel
authors.initials: OT
authors.lastname: Olaru
authors.affiliation: Oncology Unit, General Hospital of Heraklion 'Venizelio', Heraklion 71409, Greece.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Saloustros
authors.affiliation: Section of Occupational Medicine, University of Messina, I-98125 Messina, Italy.
authors.forename: Concettina
authors.initials: C
authors.lastname: Fenga
authors.affiliation: Department of Virology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece.
authors.forename: Demetrios Α
authors.initials: DΑ
authors.lastname: Spandidos
authors.affiliation: Department of Biomedical and Biotechnological Sciences, General and Clinical Pathology and Oncology Section, University of Catania, I‑95124 Catania, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Libra
authors.affiliation: Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece.
authors.forename: Aristidis M
authors.initials: AM
authors.lastname: Tsatsakis
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000495:Allosteric Site; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D002384:Catalysis; D020134:Catalytic Domain; D049109:Cell Proliferation; D002986:Clinical Trials as Topic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D020033:Protein Isoforms / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D000255:Adenosine Triphosphate; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt