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Title: An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1351349
Resource Type:
Journal Article
Resource Relation:
Journal Name: Cancer Cell; Journal Volume: 30; Journal Issue: 3
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Karoulia, Zoi, Wu, Yang, Ahmed, Tamer A., Xin, Qisheng, Bollard, Julien, Krepler, Clemens, Wu, Xuewei, Zhang, Chao, Bollag, Gideon, Herlyn, Meenhard, Fagin, James A., Lujambio, Amaia, Gavathiotis, Evripidis, and Poulikakos, Poulikos I.. An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling. United States: N. p., 2016. Web. doi:10.1016/j.ccell.2016.06.024.
Karoulia, Zoi, Wu, Yang, Ahmed, Tamer A., Xin, Qisheng, Bollard, Julien, Krepler, Clemens, Wu, Xuewei, Zhang, Chao, Bollag, Gideon, Herlyn, Meenhard, Fagin, James A., Lujambio, Amaia, Gavathiotis, Evripidis, & Poulikakos, Poulikos I.. An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling. United States. doi:10.1016/j.ccell.2016.06.024.
Karoulia, Zoi, Wu, Yang, Ahmed, Tamer A., Xin, Qisheng, Bollard, Julien, Krepler, Clemens, Wu, Xuewei, Zhang, Chao, Bollag, Gideon, Herlyn, Meenhard, Fagin, James A., Lujambio, Amaia, Gavathiotis, Evripidis, and Poulikakos, Poulikos I.. Thu . "An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling". United States. doi:10.1016/j.ccell.2016.06.024.
@article{osti_1351349,
title = {An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling},
author = {Karoulia, Zoi and Wu, Yang and Ahmed, Tamer A. and Xin, Qisheng and Bollard, Julien and Krepler, Clemens and Wu, Xuewei and Zhang, Chao and Bollag, Gideon and Herlyn, Meenhard and Fagin, James A. and Lujambio, Amaia and Gavathiotis, Evripidis and Poulikakos, Poulikos I.},
abstractNote = {},
doi = {10.1016/j.ccell.2016.06.024},
journal = {Cancer Cell},
number = 3,
volume = 30,
place = {United States},
year = {Thu Sep 01 00:00:00 EDT 2016},
month = {Thu Sep 01 00:00:00 EDT 2016}
}
  • BRAF{sup 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{sup V600E} with an IC{sub 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{sup V600E} kinase comparedmore » 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{sup 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{sup V600E}-positive cells. In B-Raf{sup 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{sup V600E}-driven tumors.« less
  • Cited by 40
  • Highlights: Black-Right-Pointing-Pointer We recently discovered a potent and selective B-Raf inhibitor, UI-152. Black-Right-Pointing-Pointer UI-152 displayed a selective cytotoxicity toward v-Ha-ras transformed cells. Black-Right-Pointing-Pointer UI-152-induced growth inhibition was largely meditated by autophagy. Black-Right-Pointing-Pointer UI-152 induced paradoxical activation of Raf-1. -- Abstract: In human cancers, B-Raf is the most frequently mutated protein kinase in the MAPK signaling cascade, making it an important therapeutic target. We recently discovered a potent and selective B-Raf inhibitor, UI-152, by using a structure-based drug design strategy. In this study, we examined whether B-Raf inhibition by UI-152 may be an effective therapeutic strategy for eliminating cancer cells transformedmore » with v-Ha-ras (Ras-NIH 3T3). UI-152 displayed selective cytotoxicity toward Ras-NIH 3T3 cells while having little to no effect on non-transformed NIH 3T3 cells. We found that treatment with UI-152 markedly increased autophagy and, to a lesser extent, apoptosis. However, inhibition of autophagy by addition of 3-MA failed to reverse the cytotoxic effects of UI-152 on Ras-NIH 3T3 cells, demonstrating that apoptosis and autophagy can act as cooperative partners to induce growth inhibition in Ras-NIH 3T3 cells treated with UI-152. Most interestingly, cell responses to UI-152 appear to be paradoxical. Here, we showed that although UI-152 inhibited ERK, it induced B-Raf binding to Raf-1 as well as Raf-1 activation. This paradoxical activation of Raf-1 by UI-152 is likely to be coupled with the inhibition of the mTOR pathway, an intracellular signaling pathway involved in autophagy. We also showed for the first time that, in multi-drug resistant cells, the combination of UI-152 with verapamil significantly decreased cell proliferation and increased autophagy. Thus, our findings suggest that the inhibition of autophagy, in combination with UI-152, offers a more effective therapeutic strategy for v-Ha-ras-transformed cells harboring wild-type B-Raf.« less
  • Substitution mutations in the BRAF serine/threonine kinase are found in a variety of human cancers. Such mutations occur in 70% of human malignant melanomas, and a single hyperactivating V600E mutation is found in the activation segment of the kinase domain and accounts for more than 90% of these mutations. Given this correlation, the molecular mechanism for BRAF regulation as well as oncogenic activation has attracted considerable interest, and activated forms of BRAF, such as BRAF{sup V600E}, have become attractive targets for small molecule inhibition. Here we report on the identification and subsequent optimization of a potent BRAF inhibitor, CS292, basedmore » on an organometallic kinase inhibitor scaffold. A cocrystal structure of CS292 in complex with the BRAF kinase domain reveals that CS292 binds to the ATP binding pocket of the kinase and is an ATP competitive inhibitor. The structure of the kinase-inhibitor complex also demonstrates that CS292 binds to BRAF in an active conformation and suggests a mechanism for regulation of BRAF by phosphorylation and BRAF{sup V600E} oncogene-induced activation. The structure of CS292 bound to the active form of the BRAF kinase also provides a novel scaffold for the design of BRAF{sup V600E} oncogene selective BRAF inhibitors for therapeutic application.« less