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

Journal Article · Wed Oct 24 04:00:00 EDT 2012 · J. Med. Chem.

DOI:https://doi.org/10.1021/jm3004416· OSTI ID:1045032

Qin, Jie; Xie, Peng; Ventocilla, Christian; Zhou, Guoqiang; Vultur, Adina; Chen, Quan; Liu, Qin; Herlyn, Meenhard; Winkler, Jeffrey; Marmorstein, Ronen ^[1]

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1. UPENN

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: OTHERNIHNCI
• OSTI ID: 1045032
• Journal Information: J. Med. Chem., Journal Name: J. Med. Chem. Journal Issue: (11) ; 06, 2012 Vol. 55; ISSN JMCMAR; ISSN 0022-2623
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
CHEMISTRY
CRYSTAL STRUCTURE
ENZYME IMMUNOASSAY
IN VITRO
LIABILITIES
MELANOMAS
NAPHTHOLS
PHOSPHOTRANSFERASES
RESIDUES
VALINE