Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor
Open accessAbstract
Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.
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Osimertinib is being studied in combination with other targeted therapies for NSCLC, such as inhibitors of the Met, Bcl-2, and MAPK pathways.
“In addition to being used alone, osimertinib is also being studied in combination with other targeted therapies for NSCLC, such as inhibitors of the Met, Bcl-2, and MAPK pathways.138–140”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [138]
Osimertinib, a third-generation EGFR inhibitor, is approved for treating advanced NSCLC that carries EGFR T790M.
“Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M”
From Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions (2018) · cites this paper as [12]
Third-generation EGFR inhibitors selectively target T790M over wild-type EGFR, including osimertinib.
“A third generation of EGFR inhibitors followed afatinib; these covalent inhibitors selectively target the T790M mutant over wild-type EGFR, and include WZ4002 (Dana–Farber Cancer Institute)43, osimertinib44,45 and rociletinib (Clovis Oncology; CO-1686)46 (Fig. 2c).”
From Advances in covalent drug discovery (2022) · cites this paper as [45]
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Cites
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., et al. (2009) · European Journal of Cancer · doi:10.1016/j.ejca.2008.10.026 · Cited by 29,534 · see citing works
Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR
Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, S., Oizumi, S., Isobe, H., Gemma, A., Harada, M., Yoshizawa, H., Kinoshita, I., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0909530 · Cited by 5,525 · see citing works
<i>EGFR</i> Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib
Kobayashi, S., Boggon, T. J., Dayaram, T., Jänne, P. A., Kocher, O., Meyerson, M., Johnson, B. E., Eck, M. J., Tenen, D. G., & Halmos, B. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa044238 · Cited by 3,964 · see citing works
Cross, D. A. E., Ashton, S. E., Ghiorghiu, S., Eberlein, C., Nebhan, C. A., Spitzler, P. J., Orme, J. P., Finlay, M. R. V., Ward, R. A., Mellor, M. J., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0337 · Cited by 2,246 · see citing works
Self-citationRational, biologically based treatment of EGFR-mutant non-small-cell lung cancer
Pao, W., & Chmielecki, J. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2947 · Cited by 1,083 · see citing works
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M
Zhou, W., Ercan, D., Chen, L., Yun, C.-H., Li, D., Capelletti, M., Cortot, A. B., Chirieac, L., Iacob, R. E., Padera, R., et al. (2009) · Nature · doi:10.1038/nature08622 · Cited by 1,013 · see citing works
Walter, A. O., Sjin, R. T. T., Haringsma, H. J., Ohashi, K., Sun, J., Lee, K., Dubrovskiy, A., Labenski, M., Zhu, Z., Wang, Z., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0314 · Cited by 620 · see citing works
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor–Resistant Disease
Ohashi, K., Maruvka, Y. E., Michor, F., & Pao, W. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.43.3912 · Cited by 467 · see citing works
Ward, R. A., Anderton, M. J., Ashton, S., Bethel, P. A., Box, M., Butterworth, S., Colclough, N., Chorley, C. G., Chuaqui, C., Cross, D. A. E., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400822z · Cited by 279 · see citing works
Self-citationDrug discovery considerations in the development of covalent inhibitors
Mah, R., Thomas, J. R., & Shafer, C. M. (2013) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2013.10.003 · Cited by 197 · see citing works
Ou, S.-H. I. (2012) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2011.11.010 · Cited by 182 · see citing works
Insulin-like Growth Factor Receptor Inhibitors: Baby or the Bathwater?
Yee, D. (2012) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djs258 · Cited by 177 · see citing works
Sjögren, E., Westergren, J., Grant, I., Hanisch, G., Lindfors, L., Lennernäs, H., Abrahamsson, B., & Tannergren, C. (2013) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2013.05.019 · Cited by 168 · see citing works
Janne, P. A., Ramalingam, S. S., Yang, J. C., Ahn, M., Kim, D., Kim, S., Planchard, D., Ohe, Y., Felip, E., Watkins, C. L., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2014.32.15_suppl.8009 · Cited by 140 · see citing works
A simple in vitro assay for assessing the reactivity of nitrile containing compounds
MacFaul, P. A., Morley, A., & Crawford, J. J. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.12.105 · Cited by 75 · see citing works
Manley, P. W., Blasco, F., Mestan, J., et al. (2013) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2013.03.038 · Cited by 53 · see citing works
Examination of Michael addition reactivity towards glutathione by transition-state calculations
Schwöbel, J. A. H., Madden, J. C., & Cronin, M. (2010) · SAR and QSAR in environmental research · doi:10.1080/1062936x.2010.528943 · Cited by 48 · see citing works
Marks, L., Borland, S. J., Philp, K. L., Ewart, L. C., Lainée, P., Skinner, M. R., Kirk, S. B., & Valentin, J. (2012) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2012.06.007 · Cited by 35 · see citing works
El‐Kattan, A. F., Poe, J., Buchholz, L., et al. (2008) · Drug Metabolism Letters · doi:10.2174/187231208784041004 · Cited by 18 · see citing works
Tang, W., Stearns, R. A., Chen, Q., et al. (2008) · Xenobiotica · doi:10.1080/00498250701744682 · Cited by 15 · see citing works
Ballard, P. G., Ashton, S. E., Cross, D. A. E., et al. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.targ-13-b212 · Cited by 6 · see citing works
Self-citationJepson (1998) · doi:10.1002/(sici)1096-9063(199812)54:4
Flagged first, then by citations
Research works printed but not linked: 2
- Walter, A. O.; Sjin, R. T. T.; Haringsma, H. J.; Ohashi, K.; Sun, J.; Lee, K.; Dubrovskiy, A.; Labenski, M.; Zhu, Z.; Wang, Z.; Sheets, M.; St Martin, T.; Karp, R.; van Kalken, D.; Chaturvedi, P.; Niu, D.; Nacht, M.; Petter, R. C.; Westlin, W.; Lin, K.; Jaw-Tsai, S.; Raponi, M.; Journal of Medicinal Chemistry Drug Annotation dx.doi.org/10.1021/jm500973a | J. Med. Chem. 2014, 57, 8249-8267 · DOI
- Clarke, E. D.; Greenhow, D. T.; Adams, D. Metabolism-related assays and their application to agrochemical research: reactivity of pesticides with glutathione and glutathione transferases. Pestic. Sci. 1998, 54, 385-393.
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Du, Z., & Lovly, C. M. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0782-4 · Cited by 1,066 · see citing works
Oxnard, G. R., Thress, K. S., Alden, R. S., Lawrance, R., Paweletz, C. P., Cantarini, M., Yang, J. C.-H., Barrett, J. C., & Jänne, P. A. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2016.66.7162 · Cited by 850 · see citing works
Advances in covalent drug discovery
Boike, L., Henning, N. J., & Nomura, D. K. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00542-z · Cited by 823 · see citing works
Ballard, P., Yates, J. W. T., Yang, Z., Kim, D.-W., Yang, J. C.-H., Cantarini, M., Pickup, K., Jordan, A., Hickey, M., Grist, M., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0399 · Cited by 718 · see citing works
Self-citationYang, Z., Yang, N., Ou, Q., Xiang, Y., Jiang, T., Wu, X., Bao, H., Tong, X., Wang, X., Shao, Y. W., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2310 · Cited by 542 · see citing works
Structure-based classification predicts drug response in EGFR-mutant NSCLC
Robichaux, J. P., Le, X., Vijayan, R. S. K., Hicks, J. K., Heeke, S., Elamin, Y. Y., Lin, H. Y., Udagawa, H., Skoulidis, F., Tran, H., et al. (2021) · Nature · doi:10.1038/s41586-021-03898-1 · Cited by 490 · see citing works
Non–Small Cell Lung Cancer, Version 6.2015
Ettinger, D. S., Wood, D. E., Akerley, W., Bazhenova, L. A., Borghaei, H., Camidge, D. R., Cheney, R. T., Chirieac, L. R., D’Amico, T. A., Demmy, T. L., et al. (2015) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2015.0071 · Cited by 478 · see citing works
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer
Bar-Peled, L., Kemper, E. K., Suciu, R. M., Vinogradova, E. V., Backus, K. M., Horning, B. D., Paul, T. A., Ichu, T.-A., Svensson, R. U., Olucha, J., et al. (2017) · Cell · doi:10.1016/j.cell.2017.08.051 · Cited by 262 · see citing works
Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain
Akçay, G., Belmonte, M. A., Aquila, B., Chuaqui, C., Hird, A. W., Lamb, M. L., Rawlins, P. B., Su, N., Tentarelli, S., Grimster, N. P., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2174 · Cited by 207 · see citing works
Courtney, K. D., Ma, Y., Diaz de Leon, A., Christie, A., Xie, Z., Woolford, L., Singla, N., Joyce, A., Hill, H., Madhuranthakam, A. J., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1459 · Cited by 188 · see citing works
Lu, X., Yu, L., Zhang, Z., Ren, X., Smaill, J. B., & Ding, K. (2018) · Medicinal Research Reviews · doi:10.1002/med.21488 · Cited by 173 · see citing works
Hirano, T., Yasuda, H., Tani, T., Hamamoto, J., Oashi, A., Ishioka, K., Arai, D., Nukaga, S., Miyawaki, M., Kawada, I., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5887 · Cited by 165 · see citing works
Wang, M., Yang, J. C.-H., Mitchell, P. L., Fang, J., Camidge, D. R., Nian, W., Chiu, C.-H., Zhou, J., Zhao, Y., Su, W.-C., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1615 · Cited by 133 · see citing works
Floc'h, N., Martin, M. J., Riess, J. W., Orme, J. P., Staniszewska, A. D., Ménard, L., Cuomo, M. E., O'Neill, D. J., Ward, R. A., Finlay, M. R. V., et al. (2018) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0758 · Cited by 115 · see citing works
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Visscher, M., Arkin, M. R., & Dansen, T. B. (2016) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2015.11.004 · Cited by 95 · see citing works
Lelais, G., Epple, R., Marsilje, T. H., Long, Y. O., McNeill, M., Chen, B., Lu, W., Anumolu, J., Badiger, S., Bursulaya, B., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01985 · Cited by 95 · see citing works
Beyond cysteine: recent developments in the area of targeted covalent inhibition
Mukherjee, H., & Grimster, N. P. (2018) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2018.05.011 · Cited by 95 · see citing works
The design and development of covalent protein-protein interaction inhibitors for cancer treatment
Cheng, S.-S., Yang, G.-J., Wang, W., Leung, C.-H., & Ma, D.-L. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00850-0 · Cited by 98 · see citing works
Planken, S., Behenna, D. C., Nair, S. K., Johnson, T. O., Nagata, A., Almaden, C., Bailey, S., Ballard, T. E., Bernier, L., Cheng, H., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01894 · Cited by 97 · see citing works
Xu, X., Mao, L., Xu, W., Tang, W., Zhang, X., Xi, B., Xu, R., Fang, X., Liu, J., Fang, C., et al. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0281 · Cited by 87 · see citing works
Basu, D., Richters, A., & Rauh, D. (2015) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2015.04.038 · Cited by 50 · see citing works
AZD9291 in <i>EGFR</i> -Mutant Advanced Non-Small-Cell Lung Cancer Patients
Remon, J., & Planchard, D. (2015) · Future Oncology · doi:10.2217/fon.15.250 · Cited by 33 · see citing works
Overcoming Resistance to AC0010, a Third Generation of EGFR Inhibitor, by Targeting c-MET and BCL-2
Xu, W., Tang, W., Li, T., Zhang, X., & Sun, Y. (2019) · Neoplasia · doi:10.1016/j.neo.2018.11.004 · Cited by 23 · see citing works
- Authors
- Finlay, M. R. V., Anderton, M., Ashton, S., Ballard, P., Bethel, P. A., Box, M. R., Bradbury, R. H., Brown, S. J., Butterworth, S., Campbell, A., Chorley, C., Colclough, N., Cross, D. A. E., Currie, G. S., Grist, M., Hassall, L., Hill, G. B., James, D., James, M., Kemmitt, P., Klinowska, T., Lamont, G., Lamont, S. G., Martin, N., McFarland, H. L., Mellor, M. J., Orme, J. P., Perkins, D., Perkins, P., Richmond, G., Smith, P., Ward, R. A., Waring, M. J., Whittaker, D., Wells, S., & Wrigley, G. L.
- Affiliations
- AstraZeneca (United Kingdom) (GB)
- Corresponding author
- Finlay, M. Raymond V.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2014-10-01
- Volume
- 57
- Issue
- 20
- Pages
- 8249-8267
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2035495099
- Cited by
- 636
- References
- 22
- Citations by year
- 2026: 49 · 2025: 69 · 2024: 57 · 2023: 51 · 2022: 62 · 2021: 50 · 2020: 54 · 2019: 51 · 2018: 54 · 2017: 55 · 2016: 48 · 2015: 34 · 2014: 2
- FWCI
- 40.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- AstraZeneca
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- osimertinib, EGFR inhibitors, T790M mutation, EGFR tyrosine kinase inhibitors, drug resistance, non-small cell lung cancer, irreversible kinase inhibitors, mutant-selective inhibitors, lead optimization
- MeSH terms
- Acrylamides, Aniline Compounds, Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Female, Humans, Indoles, Lung Neoplasms, Male, Middle Aged, Mutation, Pyrimidines, Rats, Inbred Strains, Drug Resistance, Neoplasm, Inhibitory Concentration 50, Xenograft Model Antitumor Assays, Protein Kinase Inhibitors, Mice, Chemistry Techniques, Synthetic, ErbB Receptors
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