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Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven Tumors
Open accessAbstract
Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-Raf(V600E) mutated enzyme has been observed in a number of human tumors, including melanomas. Herein we report the discovery and biological evaluation of GSK2118436, a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-Raf(V600E) human melanoma. GSK2118436 was identified as a development candidate, and early clinical results have shown significant activity in patients with B-Raf mutant melanoma.
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Mutations of the BRAF gene in human cancer
Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., et al. (2002) · Nature · doi:10.1038/nature00766 · Cited by 10,674
Improved survival with vemurafenib in melanoma with BRAF V600E mutation
Chapman, P. B., Hauschild, A., Robert, C., Haanen, J. B., Ascierto, P., Larkin, J., Dummer, R., Garbe, C., Testori, A., Maio, M., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1103782 · Cited by 7,720
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A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design
Beno, B. R., Yeung, K.-S., Bartberger, M. D., Pennington, L. D., & Meanwell, N. A. (2015) · Journal of Medicinal Chemistry · doi:10.1021/jm501853m · Cited by 772
RAF-MEK-ERK pathway in cancer evolution and treatment
Ullah, R., Yin, Q., Snell, A. H., & Wan, L. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.05.010 · Cited by 553
Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development
Donovan, K. A., Ferguson, F. M., Bushman, J. W., Eleuteri, N. A., Bhunia, D., Ryu, S., Tan, L., Shi, K., Yue, H., Liu, X., et al. (2020) · Cell · doi:10.1016/j.cell.2020.10.038 · Cited by 359
Metadata
- Authors
- Rheault, T. R., Stellwagen, J. C., Adjabeng, G. M., Hornberger, K. R., Petrov, K. G., Waterson, A. G., Dickerson, S. H., Mook, R. A., Laquerre, S. G., King, A. J., Rossanese, O. W., Arnone, M. R., Smitheman, K. N., Kane-Carson, L. S., Han, C., Moorthy, G. S., Moss, K. G., & Uehling, D. E.
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2013-02-18
- Volume
- 4
- Issue
- 3
- Pages
- 358-362
- ISSN
- 1948-5875 (ISSN-L)
- OpenAlex
- W2079104985
- Cited by
- 253
- References
- 2
- FWCI
- 6.59
- Type
- journal article
- Language
- en
- Open access
- green
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- The paper
- Rheault, T. R., Stellwagen, J. C., Adjabeng, G. M., Hornberger, K. R., Petrov, K. G., Waterson, A. G., Dickerson, S. H., Mook, R. A., Laquerre, S. G., King, A. J., Rossanese, O. W., Arnone, M. R., Smitheman, K. N., Kane-Carson, L. S., Han, C., Moorthy, G. S., Moss, K. G., & Uehling, D. E. (2013). Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven Tumors. ACS Medicinal Chemistry Letters. https://doi.org/10.1021/ml4000063
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
