4FK3

B-Raf Kinase V600E Oncogenic Mutant in Complex with PLX3203

Replaces:  3C4D

Summary for 4FK3

• Entry DOI: 10.2210/pdb4fk3/pdb
• Descriptor: Serine/threonine-protein kinase B-raf, N-{2,4-difluoro-3-[(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]phenyl}ethanesulfonamide (3 entities in total)
• Functional Keywords: transferase, serine/threonine-protein kinase, atp-binding, oncogenic v600e, kinase-kinase inhibitor complex, 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: 67092.71

Authors

Zhang, Y.,Wang, W.,Zhang, K.Y.J. (deposition date: 2012-06-12, release date: 2012-08-08, Last modification date: 2024-02-28)

Primary citation

Tsai, J.,T Lee, J.,Wang, W.,Zhang, J.,Cho, H.,Mamo, S.,Bremer, R.,Gillette, S.,Kong, J.,Haass, N.K.
Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity.
Proc.Natl.Acad.Sci.USA, 105:3041-3046, 2008

PubMed Abstract: 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 IC(50) of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 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.

PubMed: 18287029

Experimental method

X-RAY DIFFRACTION (2.65 Å)