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rdf:type |
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lifeskim:mentions |
umls-concept:C0109317,
umls-concept:C0205177,
umls-concept:C0205396,
umls-concept:C0243077,
umls-concept:C0678594,
umls-concept:C0752312,
umls-concept:C0936012,
umls-concept:C1150579,
umls-concept:C1333340,
umls-concept:C1366882,
umls-concept:C1370600,
umls-concept:C1705767,
umls-concept:C1705791,
umls-concept:C1880022
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pubmed:issue |
24
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pubmed:dateCreated |
2006-11-19
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pubmed:abstractText |
The extracellular signal-regulated kinases (ERK1 and ERK2) are important mediators of cell proliferation. Constitutive activation of the ERK proteins plays a critical role in the proliferation of many human cancers. Taking advantage of recently identified substrate docking domains on ERK2, we have used computer-aided drug design (CADD) to identify novel low molecular weight compounds that interact with ERK2 in an ATP-independent manner and disrupt substrate-specific interactions. In the current study, a CADD screen of the 3D structure of active phosphorylated ERK2 protein was used to identify inhibitory compounds. We tested 13 compounds identified by the CADD screen in ERK-specific phosphorylation, cell proliferation, and binding assays. Of the 13 compounds tested, 4 compounds strongly inhibited ERK-mediated phosphorylation of ribosomal S6 kinase-1 (Rsk-1) and/or the transcription factor Elk-1 and inhibited the proliferation of HeLa cervical carcinoma cells with IC(50) values in the 2-10 microM range. These studies demonstrate that CADD can be used to identify lead compounds for development of novel non-ATP-dependent inhibitors selective for active ERK and its interactions with substrates involved in cancer cell proliferation.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-10207078,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-10395314,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-10419844,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-10655591,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-10811804,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-10961860,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-11157753,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-11158577,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-11259830,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-11287677,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-11294822,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-11604401,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-12385501,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-12460918,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-12546562,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-12742227,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-12754209,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-14593716,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-14613031,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-14670079,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-1509259,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-15180526,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-15180527,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-15214778,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-15456252,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-15999996,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-16051177,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-16567630,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-16787369,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-2547513,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-3892003,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-6879170,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-7154081,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-8107865,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-8757935,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-923582,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-9298898,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17000106-9561267
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0960-894X
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
16
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
6281-7
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pubmed:dateRevised |
2011-8-1
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pubmed:meshHeading |
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pubmed:year |
2006
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pubmed:articleTitle |
Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure.
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pubmed:affiliation |
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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