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RDEA119/BAY 869766: A Potent, Selective, Allosteric Inhibitor of MEK1/2 for the Treatment of Cancer
Open accessAbstract
The RAS-RAF-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway provides numerous opportunities for targeted oncology therapeutics. In particular, the MEK enzyme is attractive due to high selectivity for its target ERK and the central role that activated ERK plays in driving cell proliferation. The structural, pharmacologic, and pharmacokinetic properties of RDEA119/BAY 869766, an allosteric MEK inhibitor, are presented. RDEA119/BAY 869766 is selectively bound directly to an allosteric pocket in the MEK1/2 enzymes. This compound is highly efficacious at inhibiting cell proliferation in several tumor cell lines in vitro. In vivo, RDEA119/BAY 869766 exhibits potent activity in xenograft models of melanoma, colon, and epidermal carcinoma. RDEA119/BAY 869766 exhibits complete suppression of ERK phosphorylation at fully efficacious doses in mice. RDEA119/BAY 869766 shows a tissue selectivity that reduces its potential for central nervous system–related side effects. Using pharmacokinetic and pharmacodynamic data, we show that maintaining adequate MEK inhibition throughout the dosing interval is likely more important than achieving high peak levels because greater efficacy was achieved with more frequent but lower dosing. Based on its longer half-life in humans than in mice, RDEA119/BAY 869766 has the potential for use as a once- or twice-daily oral treatment for cancer. RDEA119/BAY 869766, an exquisitely selective, orally available MEK inhibitor, has been selected for clinical development because of its potency and favorable pharmacokinetic profile. [Cancer Res 2009;69(17):6839–47]
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Citations
Cited by
Targeting RAS–ERK signalling in cancer: promises and challenges
Samatar, A. A., & Poulikakos, P. I. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4281 · Cited by 1,163
MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road
Caunt, C. J., Sale, M. J., Smith, P. D., & Cook, S. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc4000 · Cited by 606
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
EGF Receptor Is Required for KRAS-Induced Pancreatic Tumorigenesis
Ardito, C. M., Grüner, B. M., Takeuchi, K. K., Lubeseder-Martellato, C., Teichmann, N., Mazur, P. K., DelGiorno, K. E., Carpenter, E. S., Halbrook, C. J., Hall, J. C., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.07.024 · Cited by 517
Chappell, W. H., Steelman, L. S., Long, J. M., Kempf, R. C., Abrams, S. L., Franklin, R. A., Bäsecke, J., Stivala, F., Donia, M., Fagone, P., et al. (2011) · Oncotarget · doi:10.18632/oncotarget.240 · Cited by 510
Metadata
- Authors
- Iverson, C., Larson, G., Lai, C., Yeh, L.-T., Dadson, C., Weingarten, P., Appleby, T., Vo, T., Maderna, A., Vernier, J.-M., Hamatake, R., Miner, J. N., & Quart, B.
- Venue
- Cancer Research
- Published
- 2009-08-31
- Volume
- 69
- Issue
- 17
- Pages
- 6839-6847
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2070686081
- Cited by
- 183
- References
- 0
- FWCI
- 4.56
- Type
- journal article
- Language
- en
- Open access
- bronze
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- The paper
- Iverson, C., Larson, G., Lai, C., Yeh, L.-T., Dadson, C., Weingarten, P., Appleby, T., Vo, T., Maderna, A., Vernier, J.-M., Hamatake, R., Miner, J. N., & Quart, B. (2009). RDEA119/BAY 869766: A Potent, Selective, Allosteric Inhibitor of MEK1/2 for the Treatment of Cancer. Cancer Research. https://doi.org/10.1158/0008-5472.can-09-0679
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