Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 8, Pages 3041-3046Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0711741105
Keywords
cancer; cell signaling; melanoma; phosphorylation; protein kinases
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Funding
- NCI NIH HHS [CA 880999, CA 47159, R01 CA047159, T32 CA009171, T32 CA 09171] Funding Source: Medline
- NIAMS NIH HHS [AR 051448, R01 AR051886, P50 AR0504086, R01 AR051448, AR 051886] Funding Source: Medline
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BRAF(V600E) is the most frequent oncogenic protein kinase mutation known. Furthermore, inhibitors targeting active protein kinases have demonstrated significant utility in the therapeutic repertoire against cancer. Therefore, we pursued the development of specific kinase inhibitors targeting B-Raf, and the V600E allele in particular. By using a structure-guided discovery approach, a potent and selective inhibitor of active B-Raf has been discovered. PLX4720, a 7-azaindole derivative that inhibits B-Raf(V600E) with an IC50 Of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4120 preferentially inhibits the active B-Raf(V600E) kinase compared with a broad spectrum of other kinases, and potent cytotoxic effects are also exclusive to cells bearing the V600E allele. Consistent with the high degree of selectivity, ERK phosphorylation is potently inhibited by PLX4720 in B-Raf(V600E)-bearing tumor cell lines but not in cells lacking oncogenic B-Raf. In melanoma models, PLX4720 induces cell cycle arrest and apoptosis exclusively in B-Raf(V600E)-positive cells. In B-Raf(V600E)-dependent tumor xenograft models, orally dosed PLX4720 causes significant tumor growth delays, including tumor regressions, without evidence of toxicity. The work described here represents the entire discovery process, from initial identification through structural and biological studies in animal models to a promising therapeutic for testing in cancer patients bearing B-Raf(V600E)-driven tumors.
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