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

Tsai, James, Lee, John T., Wang, Weiru, Zhang, Jiazhong, Cho, Hanna, Mamo, Shumeye, Bremer, Ryan, Gillette, Sam, Kong, Jun, Haass, Nikolas K., Sproesser, Katrin, Li, Ling, Smalley, Keiran S. M., Fong, Daniel, Zhu, Yong-Liang, Marimuthu, Adhirai, Nguyen, Hoa, Lam, Billy, Liu, Jennifer, Cheung, Ivana, Rice, Julie, Suzuki, Yoshihisa, Luu, Catherine, Settachatgul, Calvin, Shellooe, Rafe, Cantwell, John, Kim, Sung-Hou, Schlessinger, Joseph, Zhang, Kam Y. J., West, Brian L., Powell, Ben, Habets, Gaston, Zhang, Chao, Ibrahim, Prabha N., Hirth, Peter, Artis, Dean R., Herlyn, Meenhard and Bollag, Gideon (2008) Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proceedings of the National Academy of Sciences of the United States of America, 105 8: 3041-3046. doi:10.1073/pnas.0711741105

Author Tsai, James
Lee, John T.
Wang, Weiru
Zhang, Jiazhong
Cho, Hanna
Mamo, Shumeye
Bremer, Ryan
Gillette, Sam
Kong, Jun
Haass, Nikolas K.
Sproesser, Katrin
Li, Ling
Smalley, Keiran S. M.
Fong, Daniel
Zhu, Yong-Liang
Marimuthu, Adhirai
Nguyen, Hoa
Lam, Billy
Liu, Jennifer
Cheung, Ivana
Rice, Julie
Suzuki, Yoshihisa
Luu, Catherine
Settachatgul, Calvin
Shellooe, Rafe
Cantwell, John
Kim, Sung-Hou
Schlessinger, Joseph
Zhang, Kam Y. J.
West, Brian L.
Powell, Ben
Habets, Gaston
Zhang, Chao
Ibrahim, Prabha N.
Hirth, Peter
Artis, Dean R.
Herlyn, Meenhard
Bollag, Gideon
Title Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
Publication date 2008-02-26
Year available 2008
Sub-type Article (original research)
DOI 10.1073/pnas.0711741105
Open Access Status Not yet assessed
Volume 105
Issue 8
Start page 3041
End page 3046
Total pages 6
Place of publication Washington, DC United States
Publisher National Academy of Sciences
Language eng
Subject 1311 Genetics
1000 General
Abstract BRAFV600E 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-RafV600E 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-RafV600E-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-RafV600E-driven tumors.
Keyword Cancer
Cell signaling
Protein kinases
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID CA 47159
AR 051448
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
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Created: Sat, 31 May 2014, 04:02:19 EST by Nikolas Haass on behalf of UQ Diamantina Institute