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From the Cover
BIOLOGICAL SCIENCES / MEDICAL SCIENCES
Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity

James Tsai^*, John T. Lee, Weiru Wang^*, Jiazhong Zhang^*, Hanna Cho^*, Shumeye Mamo^*, Ryan Bremer^*, Sam Gillette^*, Jun Kong, Nikolas K. Haass, Katrin Sproesser, Ling Li, Keiran S. M. Smalley, Daniel Fong^*, Yong-Liang Zhu^*, Adhirai Marimuthu^*, Hoa Nguyen^*, Billy Lam^*, Jennifer Liu^*, Ivana Cheung^*, Julie Rice^*, Yoshihisa Suzuki^*, Catherine Luu^*, Calvin Settachatgul^*, Rafe Shellooe^*, John Cantwell^*, Sung-Hou Kim, Joseph Schlessinger^,¶, Kam Y. J. Zhang^*, Brian L. West^*, Ben Powell^*, Gaston Habets^*, Chao Zhang^*, Prabha N. Ibrahim^*, Peter Hirth^*, Dean R. Artis^*, Meenhard Herlyn^,¶, and Gideon Bollag^*,¶

*Plexxikon, Inc., 91 Bolivar Drive, Berkeley, CA 94710; Department of Molecular and Cellular Oncogenesis, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104; 220 Calvin Laboratory, University of California, Berkeley, CA 94720; and Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520

Contributed by Joseph Schlessinger, December 15, 2007 (received for review October 15, 2007)

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. 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.

cancer | cell signaling | melanoma | phosphorylation | protein kinases

Author contributions: J.T. and J.T.L. contributed equally to this work; J.T., J.T.L., S.-H.K., J.S., K.Y.J.Z., B.L.W., G.H., C.Z., P.N.I., P.H., D.R.A., M.H., and G.B. designed research; J.T., J.T.L., W.W., J.Z., H.C., S.M., R.B., S.G., J.K., N.K.H., K.S., L.L., K.S.M.S., D.F., Y.-L.Z., A.M., H.N., B.L., J.L., I.C., J.R., Y.S., C.L., C.S., R.S., J.C., and B.P. performed research; J.T., J.T.L., W.W., J.Z., H.C., S.M., R.B., S.G., J.K., N.K.H., K.S., L.L., K.S.M.S., D.F., Y.-L.Z., A.M., H.N., B.L., J.L., I.C., J.R., Y.S., C.L., R.S., J.C., S.-H.K., J.S., K.Y.J.Z., B.L.W., G.H., C.Z., P.N.I., P.H., D.R.A., M.H., and G.B. analyzed data; and J.T., J.T.L., S.-H.K., J.S., K.Y.J.Z., B.L.W., G.H., P.N.I., D.R.A., M.H., and G.B. wrote the paper.

Conflict of interest statement: S.-H.K. and J.S. are Plexxikon founders and share holders.

Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.rcsb.org (PDB ID codes 3C4C, 3C4D, 3C4E, and 3C4F).

This article contains supporting information online at www.pnas.org/cgi/content/full/0711741105/DC1.

^¶To whom correspondence may be addressed. E-mail: joseph.schlessinger{at}yale.edu, herlynm{at}wistar.org, or gbollag{at}plexxikon.com

© 2008 by The National Academy of Sciences of the USA

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PNAS 2008 105: 2753-2754. [Full Text]