Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance
Abstract
EGFR T790M mutation leads to resistance to most of clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation have been in active clinical development, which includes osimertinib, rociletinib, HM61713, ASP8273, EGF816, and PF-06747775. On the other hand recently EGFR C797S mutation was reported to be a leading mechanism of resistance to the third-generation inhibitors. The C797S mutation appears to be an ideal target for overcoming the acquired resistance to the third generation inhibitors. This review summarizes the third generation inhibitors, synthesis, their mechanism of resistance and latest development on the discovery of a fourth-generation EGFR TKIs and U to Y allosteric strategies to combat the C797S EGFR resistance problem.
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Mavelertinib is an orally available and irreversible EGFR TKI that selectively targets various EGFR mutants with less than 50% effect against nonkinase targets.
“Mavelertinib (PF-06747775) (67) is an orally available and irreversible EGFR TKI that selectively targets various EGFR mutants, such as Del, L858R, T790M/L858R and T790M/Del, with less than 50% effect or inhibition against all nonkinase targets.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [198]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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- Authors
- Patel, H., Pawara, R., Ansari, A., & Surana, S.
- Corresponding author
- Patel, Harun
- Venue
- European Journal of Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 142
- Pages
- 32-47
- ISSN
- 0223-5234 (ISSN-L)
- OpenAlex
- W2613711128
- Cited by
- 170
- References
- 17
- Citations by year
- 2026: 11 · 2025: 20 · 2024: 16 · 2023: 19 · 2022: 23 · 2021: 20 · 2020: 18 · 2019: 18 · 2018: 21 · 2017: 4
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Science and Engineering Research Board
- Department of Science and Technology, Ministry of Science and Technology, India (/2015/002017)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- EGFR inhibitors, C797S mutation, T790M mutation, third-generation EGFR-TKI, osimertinib, rociletinib, acquired drug resistance, allosteric inhibitors, tyrosine kinase inhibitors
- MeSH terms
- Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Humans, Lung, Lung Neoplasms, Models, Molecular, Point Mutation, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, Drug Discovery, ErbB Receptors
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