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Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate)
Open accessAbstract
Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) represents a promising strategy for the discovery of a new generation of anticancer chemotherapeutics. Our synthetic efforts, beginning from the lead compound 2, were directed at improving antiproliferative activity against cancer cells as well as various drug properties. These efforts led to the discovery of N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethylsulfoxide solvate (GSK1120212, JTP-74057 DMSO solvate; 1), a selective and highly potent MEK inhibitor with improved drug properties. We further confirmed that the antiproliferative activity correlates with cellular MEK inhibition and observed significant antitumor activity with daily oral dosing of 1 in a tumor xenograft model. These qualities led to the selection of 1 for clinical development.
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Cites
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
The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901
Barrett, S. D., Bridges, A. J., Dudley, D. T., Saltiel, A. R., Fergus, J. H., Flamme, C. M., Delaney, A. M., Kaufman, M., LePage, S., Leopold, W. R., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.10.054 · Cited by 289
Cited by
FDA-approved small-molecule kinase inhibitors
Wu, P., Nielsen, T. E., & Clausen, M. H. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2015.04.005 · Cited by 1,013
Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design
Subbaiah, M. A. M., & Meanwell, N. A. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01215 · Cited by 710
Bedard, P. L., Tabernero, J., Janku, F., Wainberg, Z. A., Paz-Ares, L., Vansteenkiste, J., Van Cutsem, E., Pérez-García, J., Stathis, A., Britten, C. D., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1814 · Cited by 324
Current Development Status of MEK Inhibitors
Cheng, Y., & Tian, H. (2017) · Molecules · doi:10.3390/molecules22101551 · Cited by 291
Combination Treatment Targeting mTOR and MAPK Pathways Has Synergistic Activity in Multiple Myeloma
Sun, K., Jin, L., Karolová, J., Vorwerk, J., Hailfinger, S., Opalka, B., Zapukhlyak, M., Lenz, G., & Khandanpour, C. (2023) · Cancers · doi:10.3390/cancers15082373 · Cited by 9
Metadata
- Authors
- Abe, H., Kikuchi, S., Hayakawa, K., Iida, T., Nagahashi, N., Maeda, K., Sakamoto, J., Matsumoto, N., Miura, T., Matsumura, K., Seki, N., Inaba, T., Kawasaki, H., Yamaguchi, T., Kakefuda, R., Nanayama, T., Kurachi, H., Hori, Y., Yoshida, T., Kakegawa, J., Watanabe, Y., Gilmartin, A. G., Richter, M. C., Moss, K. G., & Laquerre, S. G.
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-02-28
- Volume
- 2
- Issue
- 4
- Pages
- 320-324
- ISSN
- 1948-5875 (ISSN-L)
- OpenAlex
- W1997304962
- Cited by
- 196
- References
- 2
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- green
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- Abe, H., Kikuchi, S., Hayakawa, K., Iida, T., Nagahashi, N., Maeda, K., Sakamoto, J., Matsumoto, N., Miura, T., Matsumura, K., Seki, N., Inaba, T., Kawasaki, H., Yamaguchi, T., Kakefuda, R., Nanayama, T., Kurachi, H., Hori, Y., Yoshida, T., . . . Laquerre, S. G. (2011). Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate). ACS Medicinal Chemistry Letters. https://doi.org/10.1021/ml200004g
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