Identification of a Novel Family of BRAF[superscript V600E] Inhibitors
- 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:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- OTHERNIHNCI
- OSTI ID:
- 1045032
- Journal Information:
- J. Med. Chem., Vol. 55, Issue (11) ; 06, 2012; ISSN 0022-2623
- Country of Publication:
- United States
- Language:
- ENGLISH
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