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Discovery of Akt Kinase Inhibitors through Structure-Based Virtual Screening and Their Evaluation as Potential Anticancer Agents
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. Fr...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346889/ https://www.ncbi.nlm.nih.gov/pubmed/25648320 http://dx.doi.org/10.3390/ijms16023202 |
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author | Chuang, Chih-Hung Cheng, Ta-Chun Leu, Yu-Ling Chuang, Kuo-Hsiang Tzou, Shey-Cherng Chen, Chien-Shu |
author_facet | Chuang, Chih-Hung Cheng, Ta-Chun Leu, Yu-Ling Chuang, Kuo-Hsiang Tzou, Shey-Cherng Chen, Chien-Shu |
author_sort | Chuang, Chih-Hung |
collection | PubMed |
description | 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 IC(50) values (for HCT-116) of 11.1 and 9.5 µM, respectively, and selectivity indices (IC(50) for HEK-293/IC(50) 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. |
format | Online Article Text |
id | pubmed-4346889 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-43468892015-04-03 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 Int J Mol Sci Article 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 IC(50) values (for HCT-116) of 11.1 and 9.5 µM, respectively, and selectivity indices (IC(50) for HEK-293/IC(50) 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. MDPI 2015-02-02 /pmc/articles/PMC4346889/ /pubmed/25648320 http://dx.doi.org/10.3390/ijms16023202 Text en © 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article 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 |
title | Discovery of Akt Kinase Inhibitors through Structure-Based Virtual Screening and Their Evaluation as Potential Anticancer Agents |
title_full | Discovery of Akt Kinase Inhibitors through Structure-Based Virtual Screening and Their Evaluation as Potential Anticancer Agents |
title_fullStr | Discovery of Akt Kinase Inhibitors through Structure-Based Virtual Screening and Their Evaluation as Potential Anticancer Agents |
title_full_unstemmed | Discovery of Akt Kinase Inhibitors through Structure-Based Virtual Screening and Their Evaluation as Potential Anticancer Agents |
title_short | Discovery of Akt Kinase Inhibitors through Structure-Based Virtual Screening and Their Evaluation as Potential Anticancer Agents |
title_sort | discovery of akt kinase inhibitors through structure-based virtual screening and their evaluation as potential anticancer agents |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346889/ https://www.ncbi.nlm.nih.gov/pubmed/25648320 http://dx.doi.org/10.3390/ijms16023202 |
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