Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure.

Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure. Research Abstract Details 

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Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure. Abstract Text:

Fengming Chen,Chad N Hancock,Alba T Macias,Joseph Joh,Kimberly Still,Shijun Zhong,Alexander D MacKerell,Paul Shapiro,

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.

Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure. Publishing Authors By Initials

F Chen,CN Hancock,AT Macias,J Joh,K Still,S Zhong,AD MacKerell,P Shapiro,

For similar chemical actions and uses: pharmacologic actions: molecular mechanisms of pharmacological action: enzyme inhibitors: protein kinase inhibitors research abstracts see: chemical actions and uses: pharmacologic actions: molecular mechanisms of pharmacological action: enzyme inhibitors: protein kinase inhibitors research

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Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Bioorganic & medicinal chemistry letters

VOLUME: 16

Page Numbers: 6281-7

Journal Abbreviation: Bioorg. Med. Chem. Lett.

ISSN: 0960-894X

DAY: 26

MONTH: 09

YEAR: 2006

Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9107377

Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure. Keywords Mesh Terms:

KEYWORDS: Protein Kinase Inhibitors

MESH TERMS: pharmacology

Chemical & Substance for Abstract: Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure. Information

Substance Name: Mitogen-Activated Protein Kinase 3

Registry Number: EC 2.7.1.37

Grant and Affiliation Information for Characterization of ATP-independent ERK inhibitors identified through in silico analysis of the active ERK2 structure.

AFFILIATION: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.

Country: England

AGENCY: United States NCI

GRANT: R21 CA105299-02

ACRONYM: CA

MEDLINETA: Bioorg Med Chem Lett

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