Identification of a Novel family of BRAF V600E inhibitors

The Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 04/2012; 55(11):5220-30. DOI: 10.1021/jm3004416
Source: PubMed


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.

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    • "As seen from Figure 4, between 25%–40% of the structures identified with significant clustering had fewer clusters under the GraphPAC methodology as compared to the linear NMC algorithm with the vast majority of these structures corresponding to BRAF, HRAS and TP53. Here we consider a representative example, the 4E26 structure [74] for BRAF when analyzed using the farthest insertion method (Figure 8). As iPAC identified even more clusters than NMC, we compare GraphPAC to NMC in this section when showing that fewer mutational clusters is of benefit. "
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