Open Access

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

  • Authors:
    • George Mihai Nitulescu
    • Denisa Margina
    • Petras Juzenas
    • Qian Peng
    • Octavian Tudorel Olaru
    • Emmanouil Saloustros
    • Concettina Fenga
    • Demetrios Α. Spandidos
    • Massimo Libra
    • Aristidis M. Tsatsakis
  • View Affiliations

  • Published online on: December 24, 2015     https://doi.org/10.3892/ijo.2015.3306
  • Pages: 869-885
  • Copyright: © Nitulescu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


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.
View Figures
View References

Related Articles

Journal Cover

March 2016
Volume 48 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
APA
Nitulescu, G.M., Margina, D., Juzenas, P., Peng, Q., Olaru, O.T., Saloustros, E. ... Tsatsakis, A.M. (2016). Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review). International Journal of Oncology, 48, 869-885. https://doi.org/10.3892/ijo.2015.3306
MLA
Nitulescu, G. M., Margina, D., Juzenas, P., Peng, Q., Olaru, O. T., Saloustros, E., Fenga, C., Spandidos, D. Α., Libra, M., Tsatsakis, A. M."Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review)". International Journal of Oncology 48.3 (2016): 869-885.
Chicago
Nitulescu, G. M., Margina, D., Juzenas, P., Peng, Q., Olaru, O. T., Saloustros, E., Fenga, C., Spandidos, D. Α., Libra, M., Tsatsakis, A. M."Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review)". International Journal of Oncology 48, no. 3 (2016): 869-885. https://doi.org/10.3892/ijo.2015.3306