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Title: Identification of a Novel Family of BRAF[superscript V600E] Inhibitors

Abstract

The BRAF oncoprotein is mutated in about half of malignant melanomas and other cancers, and a kinase activating single valine to glutamate substitution at residue 600 (BRAF{sup V600E}) accounts for over 90% of BRAF-mediated cancers. Several BRAF{sup V600E} inhibitors have been developed, although they harbor some liabilities, thus motivating the development of other BRAF{sup V600E} inhibitor options. We report here the use of an ELISA based high-throughput screen to identify a family of related quinolol/naphthol compounds that preferentially inhibit BRAF{sup V600E} over BRAF{sup WT} and other kinases. We also report the X-ray crystal structure of a BRAF/quinolol complex revealing the mode of inhibition, employ structure-based medicinal chemistry efforts to prepare naphthol analogues that inhibit BRAF{sup V600E} in vitro with IC{sub 50} values in the 80-200 nM range under saturating ATP concentrations, and demonstrate that these compounds inhibit MAPK signaling in melanoma cells. Prospects for improving the potency and selectivity of these inhibitors are discussed.

Authors:
; ; ; ; ; ; ; ; ;  [1]
  1. (UPENN)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
OTHERNIHNCI
OSTI Identifier:
1045032
Resource Type:
Journal Article
Journal Name:
J. Med. Chem.
Additional Journal Information:
Journal Volume: 55; Journal Issue: (11) ; 06, 2012; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CHEMISTRY; CRYSTAL STRUCTURE; ENZYME IMMUNOASSAY; IN VITRO; LIABILITIES; MELANOMAS; NAPHTHOLS; PHOSPHOTRANSFERASES; RESIDUES; VALINE

Citation Formats

Qin, Jie, Xie, Peng, Ventocilla, Christian, Zhou, Guoqiang, Vultur, Adina, Chen, Quan, Liu, Qin, Herlyn, Meenhard, Winkler, Jeffrey, and Marmorstein, Ronen. Identification of a Novel Family of BRAF[superscript V600E] Inhibitors. United States: N. p., 2012. Web. doi:10.1021/jm3004416.
Qin, Jie, Xie, Peng, Ventocilla, Christian, Zhou, Guoqiang, Vultur, Adina, Chen, Quan, Liu, Qin, Herlyn, Meenhard, Winkler, Jeffrey, & Marmorstein, Ronen. Identification of a Novel Family of BRAF[superscript V600E] Inhibitors. United States. doi:10.1021/jm3004416.
Qin, Jie, Xie, Peng, Ventocilla, Christian, Zhou, Guoqiang, Vultur, Adina, Chen, Quan, Liu, Qin, Herlyn, Meenhard, Winkler, Jeffrey, and Marmorstein, Ronen. Wed . "Identification of a Novel Family of BRAF[superscript V600E] Inhibitors". United States. doi:10.1021/jm3004416.
@article{osti_1045032,
title = {Identification of a Novel Family of BRAF[superscript V600E] Inhibitors},
author = {Qin, Jie and Xie, Peng and Ventocilla, Christian and Zhou, Guoqiang and Vultur, Adina and Chen, Quan and Liu, Qin and Herlyn, Meenhard and Winkler, Jeffrey and Marmorstein, Ronen},
abstractNote = {The BRAF oncoprotein is mutated in about half of malignant melanomas and other cancers, and a kinase activating single valine to glutamate substitution at residue 600 (BRAF{sup V600E}) accounts for over 90% of BRAF-mediated cancers. Several BRAF{sup V600E} inhibitors have been developed, although they harbor some liabilities, thus motivating the development of other BRAF{sup V600E} inhibitor options. We report here the use of an ELISA based high-throughput screen to identify a family of related quinolol/naphthol compounds that preferentially inhibit BRAF{sup V600E} over BRAF{sup WT} and other kinases. We also report the X-ray crystal structure of a BRAF/quinolol complex revealing the mode of inhibition, employ structure-based medicinal chemistry efforts to prepare naphthol analogues that inhibit BRAF{sup V600E} in vitro with IC{sub 50} values in the 80-200 nM range under saturating ATP concentrations, and demonstrate that these compounds inhibit MAPK signaling in melanoma cells. Prospects for improving the potency and selectivity of these inhibitors are discussed.},
doi = {10.1021/jm3004416},
journal = {J. Med. Chem.},
issn = {0022-2623},
number = (11) ; 06, 2012,
volume = 55,
place = {United States},
year = {2012},
month = {10}
}