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6-Substituted-4-(3-bromophenylamino)quinazolines as Putative Irreversible Inhibitors of the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor (HER-2) Tyrosine Kinases with Enhanced Antitumor Activity
Open accessAbstract
A series of new 6-substituted-4-(3-bromophenylamino)quinazoline derivatives that may function as irreversible inhibitors of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases have been prepared. These inhibitors have, at the C-6 position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(3-bromophenylamino)quinazoline with unsaturated acid chlorides or mixed anhydrides. We show that attaching a basic functional group onto the Michael acceptor results in greater reactivity, due to intramolecular catalysis of the Michael addition and/or an inductive effect of the protonated basic group. This, along with improved water solubility, results in compounds with enhanced biological properties. We present molecular modeling and experimental evidence that these inhibitors interact covalently with the target enzymes. One compound, 16a, was shown to have excellent oral activity in a human epidermoid carcinoma (A431) xenograft model in nude mice.
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Cited by
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Sergina, N. V., Rausch, M., Wang, D., Blair, J., Hann, B., Shokat, K. M., & Moasser, M. M. (2007) · Nature · doi:10.1038/nature05474 · Cited by 991
Discovery of Selective Irreversible Inhibitors for Bruton’s Tyrosine Kinase
Pan, Z., Scheerens, H., Li, S., Schultz, B. E., Sprengeler, P. A., Burrill, L. C., Mendonca, R. V., Sweeney, M. D., Scott, K. C. K., Grothaus, P. G., et al. (2007) · ChemMedChem · doi:10.1002/cmdc.200600221 · Cited by 674
Jackson, P. A., Widen, J. C., Harki, D. A., & Brummond, K. M. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00788 · Cited by 588
Khan, I., Ibrar, A., Abbas, N., & Saeed, A. (2014) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2014.02.005 · Cited by 469
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Erlanson, D. A., Wells, J. A., & Braisted, A. C. (2004) · Annual Review of Biophysics and Biomolecular Structure · doi:10.1146/annurev.biophys.33.110502.140409 · Cited by 385
Metadata
- Authors
- Tsou, H.-R., Mamuya, N., Johnson, B. D., Reich, M. F., Gruber, B. C., Ye, F., Nilakantan, R., Shen, R., Discafani, C., DeBlanc, R., Davis, R., Koehn, F. E., Greenberger, L. M., Wang, Y.-F., & Wissner, A.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2001-07-14
- Volume
- 44
- Issue
- 17
- Pages
- 2719-2734
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2101245114
- Cited by
- 271
- References
- 0
- FWCI
- 6.69
- Type
- journal article
- Language
- en
- Open access
- green
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- CoChat. (2026). Citation check: 6-Substituted-4-(3-bromophenylamino)quinazolines as Putative Irreversible Inhibitors of the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor (HER-2) Tyrosine Kinases with Enhanced Antitumor Activity. https://app.cochat.ai/papers/10.1021/jm0005555
- The paper
- Tsou, H.-R., Mamuya, N., Johnson, B. D., Reich, M. F., Gruber, B. C., Ye, F., Nilakantan, R., Shen, R., Discafani, C., DeBlanc, R., Davis, R., Koehn, F. E., Greenberger, L. M., Wang, Y.-F., & Wissner, A. (2001). 6-Substituted-4-(3-bromophenylamino)quinazolines as Putative Irreversible Inhibitors of the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor (HER-2) Tyrosine Kinases with Enhanced Antitumor Activity. Journal of Medicinal Chemistry. https://doi.org/10.1021/jm0005555
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