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    Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents.

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    Authors
    Niculescu-Duvaz, D
    Niculescu-Duvaz, I
    Suijkerbuijk, B
    Ménard, D
    Zambon, A
    Davies, L
    Pons, J
    Whittaker, S
    Marais, Richard
    Springer, C
    Affiliation
    The Institute of Cancer Research, Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
    Issue Date
    2013-03-01
    
    Metadata
    Show full item record
    Abstract
    The RAS-RAF-MEK-ERK pathway is hyperactivated in 30% of human cancers. BRAF is a serine-threonine kinase, belonging to this pathway that is mutated with high frequency in human melanoma and other cancers thus BRAF is an important therapeutic target in melanoma. We have designed inhibitors of BRAF based on 2,4,5-trisubstituted imidazoles with naphthyl and benzothiophene-4-substituents. Two compounds were discovered to be potent BRAF inhibitors: 1-(6-{2-[4-(2-dimethylamino-ethoxy)phenyl]-5-(pyridin-4-yl)-1H-imidazol-4-yl} benzo[b]thiophen-3-yl)-2,2,2-trifluoroethanol (1i) with BRAF IC(50)=190 nM and with cellular GI(50)=2100 nM, and 6-{2-[4-(2-dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-naphthalen-1-ol (1q) with IC(50)=9 nM and GI(50)=220 nM.
    Citation
    Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents. 2013, 21 (5):1284-304 Bioorg Med Chem
    Journal
    Bioorganic & Medicinal Chemistry
    URI
    http://hdl.handle.net/10541/279093
    DOI
    10.1016/j.bmc.2012.12.035
    PubMed ID
    23376011
    Type
    Article
    Language
    en
    ISSN
    1464-3391
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.bmc.2012.12.035
    Scopus Count
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    All Paterson Institute for Cancer Research

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