4E26

BRAF in complex with an organic inhibitor 7898734

Summary for 4E26

• Entry DOI: 10.2210/pdb4e26/pdb
• Descriptor: Serine/threonine-protein kinase B-raf, 5-chloro-7-[(R)-furan-2-yl(pyridin-2-ylamino)methyl]quinolin-8-ol (3 entities in total)
• Functional Keywords: kinase, inhibitor, oncoprotein, melanoma, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (By similarity): P15056
• Total number of polymer chains: 2
• Total formula weight: 71138.84

Authors

Qin, J.,Xie, P.,Ventocilla, C.,Zhou, G.,Vultur, A.,Chen, Q.,Herlyn, M.,Winkler, J.,Marmorstein, R. (deposition date: 2012-03-07, release date: 2012-05-09, Last modification date: 2024-02-28)

Primary citation

Qin, J.,Xie, P.,Ventocilla, C.,Zhou, G.,Vultur, A.,Chen, Q.,Liu, Q.,Herlyn, M.,Winkler, J.,Marmorstein, R.
Identification of a Novel Family of BRAF(V600E) Inhibitors.
J.Med.Chem., 55:5220-5230, 2012

PubMed 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(V600E)) accounts for over 90% of BRAF-mediated cancers. Several BRAF(V600E) inhibitors have been developed, although they harbor some liabilities, thus motivating the development of other BRAF(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(V600E) over BRAF(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(V600E) in vitro with IC(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.

PubMed: 22537109
DOI: 10.1021/jm3004416

Experimental method

X-RAY DIFFRACTION (2.55 Å)