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Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Overview of attention for article published in Proceedings of the National Academy of Sciences of the United States of America, June 2013
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2 tweeters

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75 Mendeley
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2 CiteULike
Title
Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function
Published in
Proceedings of the National Academy of Sciences of the United States of America, June 2013
DOI 10.1073/pnas.1300016110
Pubmed ID
Authors

H. J. Hocker, K.-J. Cho, C.-Y. K. Chen, N. Rambahal, S. R. Sagineedu, K. Shaari, J. Stanslas, J. F. Hancock, A. A. Gorfe

Abstract

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 small-molecule 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.

Twitter Demographics

The data shown below were collected from the profiles of 2 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 75 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United States 2 3%
Malaysia 2 3%
United Kingdom 1 1%
Denmark 1 1%
India 1 1%
Unknown 68 91%

Demographic breakdown

Readers by professional status Count As %
Researcher 18 24%
Student > Ph. D. Student 16 21%
Professor > Associate Professor 7 9%
Student > Postgraduate 6 8%
Student > Bachelor 6 8%
Other 22 29%
Readers by discipline Count As %
Agricultural and Biological Sciences 23 31%
Chemistry 20 27%
Biochemistry, Genetics and Molecular Biology 9 12%
Medicine and Dentistry 7 9%
Pharmacology, Toxicology and Pharmaceutical Science 6 8%
Other 10 13%

Attention Score in Context

This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 05 September 2013.
All research outputs
#7,424,151
of 12,365,166 outputs
Outputs from Proceedings of the National Academy of Sciences of the United States of America
#67,432
of 77,340 outputs
Outputs of similar age
#73,320
of 150,382 outputs
Outputs of similar age from Proceedings of the National Academy of Sciences of the United States of America
#828
of 1,033 outputs
Altmetric has tracked 12,365,166 research outputs across all sources so far. This one is in the 37th percentile – i.e., 37% of other outputs scored the same or lower than it.
So far Altmetric has tracked 77,340 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 22.0. This one is in the 11th percentile – i.e., 11% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 150,382 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 48th percentile – i.e., 48% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 1,033 others from the same source and published within six weeks on either side of this one. This one is in the 18th percentile – i.e., 18% of its contemporaries scored the same or lower than it.