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

  title={Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review)},
  author={George Mihai Nițulescu and Denisa Margină and Petras Juzenas and Qian Peng and Octavian Tudorel Olaru and Emmanouil Saloustros and Concettina Fenga and Demetrios A. Spandidos and Massimo Libra and Aristidis M. Tsatsakis},
  journal={International Journal of Oncology},
  pages={869 - 885}
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… 
Akt Pathway Inhibitors.
Preclinical data reveals robust mechanistic rationales evaluating their effects in various cancer types with hyperactivated Akt signaling, including ipatasertib, which is known as the first allosteric Akt inhibitor to enter clinical development and is mechanistically characterized as a PH-domain dependent inhibitor, non-competitive with ATP.
The Akt pathway in oncology therapy and beyond (Review)
This review presents key features of Akt structure and functions, and presents the progress ofAkt inhibitors in regards to drug development, and their preclinical and clinical activity in regard to therapeutic efficacy and safety for patients.
Targeting AKT in ER-Positive HER2-Negative Metastatic Breast Cancer: From Molecular Promises to Real Life Pitfalls?
The scope of the present review is to focus on the pivotal role of AKT in metastatic breast cancer through the analysis of its molecular features and to discuss clinical implications and remaining challenges in the treatment of HR-positive metastatic Breast cancer.
Anticancer agents based on vulnerable components in a signalling pathway.
Traditional cancer treatment includes surgery, chemotherapy, radiotherapy and immunotherapy that are beneficially clinically, but are associated with drawbacks such as drug resistance and side
Protein Kinase Targets in Breast Cancer
This review analyzes studies published to date about novel small-molecule kinase inhibitors against various malignancies and evaluates if they would be useful to develop new treatment strategies for breast cancer patients.
A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity
The utility of individual AKT inhibitors, both as drugs and as chemical probes, and the benefit of AKT inhibitor pharmacological diversity in providing a repertoire of context-specific therapeutic options are illustrated.
The next generation of PI3K-Akt-mTOR pathway inhibitors in breast cancer cohorts.
New Advances in Targeted Therapy of HER2-Negative Breast Cancer
The potential targets that may be used for breast cancer treatment from the aspects of PI3K/AKT signaling pathway, DDR, angiogenesis, the cell cycle, breast cancer stem cells, etc., are described and possible inhibitors for the treatment of HER2-negative breast cancer are explored.


Inhibition of Akt with small molecules and biologics: historical perspective and current status of the patent landscape
It is not yet clear which mechanism of Akt inhibition will be optimal in humans, or which Akt isoforms to inhibit, or whether a small molecule or biologic agent will be best, but data to all of these points will be available in the near future.
Recent development of anticancer therapeutics targeting Akt.
H successes and challenges to date on the development of anticancer agents modulating the Akt pathway in recent patents are highlighted as well as the methods employed for this task.
Activation of the PI3K/Akt pathway and chemotherapeutic resistance.
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    Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy
  • 2002
Discovery of Novel AKT Inhibitors with Enhanced Anti-Tumor Effects in Combination with the MEK Inhibitor
Investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels.
Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors.
Biological studies with one 6,7-dihydro-5H-cyclopenta[d]pyrimidine compound, 28 (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway is activated.
Optimal classes of chemotherapeutic agents sensitized by specific small-molecule inhibitors of akt in vitro and in vivo.
Findings provide important guidance in selecting appropriate classes of chemotherapeutic agents for combination with Akt inhibitors in cancer treatment.
Targeting Activated Akt with GDC-0068, a Novel Selective Akt Inhibitor That Is Efficacious in Multiple Tumor Models
GDC-0068 is a highly selective, orally bioavailable Akt kinase inhibitor that shows pharmacodynamic inhibition of Akt signaling and robust antitumor activity in human cancer cells in vitro and in vivo.
Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo
The development of a series of potent and selective indazole-pyridine based Akt inhibitors is reported, which inhibit Akt-dependent signal transduction in cells and in vivo in a dose-responsive manner and slow the progression of tumors when used as monotherapy or in combination with paclitaxel or rapamycin.
The Akt inhibitor triciribine sensitizes prostate carcinoma cells to TRAIL‐induced apoptosis
TCN inhibits Akt phosphorylation at Thr308 and Ser473 and Akt activity in the human prostate cancer cell line PC‐3, which might open a promising therapeutic approach for the elimination of hormone‐refractory prostate cancers, which are largely resistant to conventional DNA damaging anticancer drugs or irradiation.
AT7867 Is a Potent and Oral Inhibitor of AKT and p70 S6 Kinase That Induces Pharmacodynamic Changes and Inhibits Human Tumor Xenograft Growth
The data suggest that the novel strategy of AKT and p70S6K blockade may have therapeutic value and supports further evaluation of AT7867 as a single-agent anticancer strategy.