Discovery of akt kinase inhibitors through structure-based virtual screening and their evaluation as potential anticancer agents

Chih Hung Chuang, Ta Chun Cheng, Yu Ling Leu, Kuo Hsiang Chuang, Shey Cherng Tzou, Chien Shu Chen

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Akt acts as a pivotal regulator in the PI3K/Akt signaling pathway and represents a potential drug target for cancer therapy. To search for new inhibitors of Akt kinase, we performed a structure-based virtual screening using the DOCK 4.0 program and the X-ray crystal structure of human Akt kinase. From the virtual screening, 48 compounds were selected and subjected to the Akt kinase inhibition assay. Twenty-six of the test compounds showed more potent inhibitory effects on Akt kinase than the reference compound, H-89. These 26 compounds were further evaluated for their cytotoxicity against HCT-116 human colon cancer cells and HEK-293 normal human embryonic kidney cells. Twelve compounds were found to display more potent or comparable cytotoxic activity compared to compound H-89 against HCT-116 colon cancer cells. The best results were obtained with Compounds a46 and a48 having IC50 values (for HCT-116) of 11.1 and 9.5 µM, respectively, and selectivity indices (IC50 for HEK-293/IC50 for HCT-116) of 12.5 and 16.1, respectively. Through structure-based virtual screening and biological evaluations, we have successfully identified several new Akt inhibitors that displayed cytotoxic activity against HCT-116 human colon cancer cells. Especially, Compounds a46 and a48 may serve as useful lead compounds for further development of new anticancer agents.

Original languageEnglish
Pages (from-to)3202-3212
Number of pages11
JournalInternational Journal of Molecular Sciences
Volume16
Issue number2
DOIs
Publication statusPublished - Feb 2 2015

Fingerprint

Antineoplastic Agents
inhibitors
Screening
Phosphotransferases
screening
cancer
Cells
Colonic Neoplasms
Inhibitory Concentration 50
evaluation
Lead compounds
Cytotoxicity
lead compounds
HEK293 Cells
Assays
regulators
kidneys
Crystal structure
Phosphatidylinositol 3-Kinases
X rays

Keywords

  • Akt kinase
  • Cancer
  • Docking
  • Inhibitors
  • Virtual screening

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Spectroscopy
  • Inorganic Chemistry
  • Catalysis
  • Molecular Biology
  • Computer Science Applications

Cite this

Discovery of akt kinase inhibitors through structure-based virtual screening and their evaluation as potential anticancer agents. / Chuang, Chih Hung; Cheng, Ta Chun; Leu, Yu Ling; Chuang, Kuo Hsiang; Tzou, Shey Cherng; Chen, Chien Shu.

In: International Journal of Molecular Sciences, Vol. 16, No. 2, 02.02.2015, p. 3202-3212.

Research output: Contribution to journalArticle

Chuang, Chih Hung ; Cheng, Ta Chun ; Leu, Yu Ling ; Chuang, Kuo Hsiang ; Tzou, Shey Cherng ; Chen, Chien Shu. / Discovery of akt kinase inhibitors through structure-based virtual screening and their evaluation as potential anticancer agents. In: International Journal of Molecular Sciences. 2015 ; Vol. 16, No. 2. pp. 3202-3212.
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