Reference Detail

Ref Type

Journal Article

PMID

(18287029)

Authors

Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, Sproesser K, Li L, Smalley KS, Fong D, Zhu YL, Marimuthu A, Nguyen H, Lam B, Liu J, Cheung I, Rice J, Suzuki Y, Luu C, Settachatgul C, Shellooe R, Cantwell J, Kim SH, Schlessinger J, Zhang KY, West BL, Powell B, Habets G, Zhang C, Ibrahim PN, Hirth P, Artis DR, Herlyn M, Bollag G

Title

Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America	105	8	2008 Feb 26	3041-6	Proc Natl Acad Sci U S A

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
PLX4720	PLX4720	21	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
PLX4720		PLX-4720\|PLX 4720	BRAF Inhibitor 25	PLX4720 is a 7-azaindole derivative and RAF kinase inhibitor with greater affinity for BRAF V600E than BRAF wild-type, which may induce cell cycle arrest and apoptosis, and lead to tumor growth inhibition and regression (PMID: 18287029).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF wild-type	melanoma	resistant	PLX4720	Preclinical - Cell line xenograft	Actionable	In a preclinical study, PLX4720 did not inhibit growth of BRAF wild-type melanoma cells in culture or in cell line xenograft models (PMID: 18287029).	18287029
BRAF V600E	colon cancer	sensitive	PLX4720	Preclinical - Cell line xenograft	Actionable	In a preclinical study, PLX4720 inhibited growth of colon cancer cells harboring BRAF V600E in culture and in cell line xenograft models (PMID: 18287029).	18287029
BRAF V600E	melanoma	sensitive	PLX4720	Preclinical - Cell line xenograft	Actionable	In a preclinical study, PLX4720 inhibited growth of melanoma cells harboring BRAF V600E in culture and in cell line xenograft models (PMID: 18287029).	18287029