Staff View: Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Aberrant signaling by oncogenic mutant rat sarcoma (Ras)proteins occurs in ∼15% of all human tumors, yet direct inhibition of Ras by small molecules has remained elusive. Recently, several smallmolecule ligands have been discovered that directly bind Ras and inhibit its function by interfering with...

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Main Authors:	Hocker, Harrison J., Cho, Kwang Jin, Chen, Chung Ying K., Rambahal, Nandini, Sagineedu, Sreenivasa Rao, Shaari, Khozirah, Stanslas, Johnson, Hancock, John F., Gorfe, Alemayehu A.
Format:	Book Section
Published:	National Academy of Sciences 2013
Online Access:	http://psasir.upm.edu.my/id/eprint/29800/
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spelling	my.upm.eprints.298002014-12-27T10:56:35Z http://psasir.upm.edu.my/id/eprint/29800/ Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function Hocker, Harrison J. Cho, Kwang Jin Chen, Chung Ying K. Rambahal, Nandini Sagineedu, Sreenivasa Rao Shaari, Khozirah Stanslas, Johnson Hancock, John F. Gorfe, Alemayehu A. Aberrant signaling by oncogenic mutant rat sarcoma (Ras)proteins occurs in ∼15% of all human tumors, yet direct inhibition of Ras by small molecules has remained elusive. Recently, several smallmolecule ligands have been discovered that directly bind Ras and inhibit its function by interfering with exchange factor binding. However, it is unclear whether, or how, these ligands could lead to drugs that act against constitutively active oncogenic mutant Ras. Using a dynamics-based pocket identification scheme, ensemble docking, and innovative cell-based assays, here we show that andrographolide (AGP)-a bicyclic diterpenoid lactone isolated from Andrographis paniculata-and its benzylidene derivatives bind to transient pockets on Kirsten-Ras (K-Ras) and inhibit GDP-GTP exchange. As expected for inhibitors of exchange factor binding, AGP derivatives reduced GTP loading of wild-type K-Ras in response to acute EGF stimulation with a concomitant reduction in MAPK activation. Remarkably, however, prolonged treatment with AGP derivatives also reduced GTP loading of, and signal transmission by, oncogenic mutant K-RasG12V. In sum, the combined analysis of our computational and cell biology results show that AGP derivatives directly bind Ras, block GDP-GTP exchange, and inhibit both wild-type and oncogenic K-Ras signaling. Importantly, our findings not only show that nucleotide exchange factors are required for oncogenic Ras signaling but also demonstrate that inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras. National Academy of Sciences 2013-06-18 Book Section PeerReviewed Hocker, Harrison J. and Cho, Kwang Jin and Chen, Chung Ying K. and Rambahal, Nandini and Sagineedu, Sreenivasa Rao and Shaari, Khozirah and Stanslas, Johnson and Hancock, John F. and Gorfe, Alemayehu A. (2013) Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function. In: Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, United States of America, pp. 10201-10206. 10.1073/pnas.1300016110
institution	Universiti Putra Malaysia
building	UPM Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	Universiti Putra Malaysia
content_source	UPM Institutional Repository
url_provider	http://psasir.upm.edu.my/
description	Aberrant signaling by oncogenic mutant rat sarcoma (Ras)proteins occurs in ∼15% of all human tumors, yet direct inhibition of Ras by small molecules has remained elusive. Recently, several smallmolecule ligands have been discovered that directly bind Ras and inhibit its function by interfering with exchange factor binding. However, it is unclear whether, or how, these ligands could lead to drugs that act against constitutively active oncogenic mutant Ras. Using a dynamics-based pocket identification scheme, ensemble docking, and innovative cell-based assays, here we show that andrographolide (AGP)-a bicyclic diterpenoid lactone isolated from Andrographis paniculata-and its benzylidene derivatives bind to transient pockets on Kirsten-Ras (K-Ras) and inhibit GDP-GTP exchange. As expected for inhibitors of exchange factor binding, AGP derivatives reduced GTP loading of wild-type K-Ras in response to acute EGF stimulation with a concomitant reduction in MAPK activation. Remarkably, however, prolonged treatment with AGP derivatives also reduced GTP loading of, and signal transmission by, oncogenic mutant K-RasG12V. In sum, the combined analysis of our computational and cell biology results show that AGP derivatives directly bind Ras, block GDP-GTP exchange, and inhibit both wild-type and oncogenic K-Ras signaling. Importantly, our findings not only show that nucleotide exchange factors are required for oncogenic Ras signaling but also demonstrate that inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras.
format	Book Section
author	Hocker, Harrison J. Cho, Kwang Jin Chen, Chung Ying K. Rambahal, Nandini Sagineedu, Sreenivasa Rao Shaari, Khozirah Stanslas, Johnson Hancock, John F. Gorfe, Alemayehu A.
spellingShingle	Hocker, Harrison J. Cho, Kwang Jin Chen, Chung Ying K. Rambahal, Nandini Sagineedu, Sreenivasa Rao Shaari, Khozirah Stanslas, Johnson Hancock, John F. Gorfe, Alemayehu A. Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function
author_facet	Hocker, Harrison J. Cho, Kwang Jin Chen, Chung Ying K. Rambahal, Nandini Sagineedu, Sreenivasa Rao Shaari, Khozirah Stanslas, Johnson Hancock, John F. Gorfe, Alemayehu A.
author_sort	Hocker, Harrison J.
title	Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function
title_short	Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function
title_full	Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function
title_fullStr	Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function
title_full_unstemmed	Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function
title_sort	andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic ras function
publisher	National Academy of Sciences
publishDate	2013
url	http://psasir.upm.edu.my/id/eprint/29800/
_version_	1643829868630114304
score	13.211869

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

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