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Novel mutant-selective EGFR kinase inhibitors against EGFR T790M
Open accessAbstract
The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.
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In the citing paper
“C797 is located opposite T790 in the ATP binding pocket and forms a covalent bond with all third-generation TKIs and is necessary for the inhibitor to suppress EGFR (21).”
From The Allelic Context of the C797S Mutation Acquired upon Treatment with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies (2015) · cites this paper as [21]
Experimental — accuracy not yet measuredIn the citing paper
“In 2009, Pasi et al. identified a series of covalent pyrimidine EGFR inhibitors, including WZ 3146, WZ 4002, and WZ 8040, through screening a library of irreversible kinase inhibitors specific to EGFRT790M.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [203]
In the citing paper
“These agents are designed to specifically inhibit mutant EGFR (ie, 19del-EGFR, L858R-EGFR and/or T790M+EGFR), sparing the WT receptor.14–18”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [14]
In the citing paper
“The presence of the T790M mutation was observed in approximately 50% of the cases in which biopsy was obtained at the time of relapse following gefitinib or erlotinib treatment in patients with the exon 19 deletion or the L858R EGFR mutation.”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [14]
In the citing paper
“AZD9291 has a distinct chemical structure from the other third-generation TKIs, WZ4002 (34) and CO-1686 (35).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [34]
In the citing paper
“This approach has previously led to identification of clinically relevant drug resistance mutations to EGFR TKIs (30, 31).”
From Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors (2017) · cites this paper as [30]
In the citing paper
“Thus, the T790M structural alteration in essence “enabled” discovery of inhibitors that selectively inhibit T790M–bearing mutants, when in association with L858R or exon 19 deletions, relative to WT EGFR 58,59.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [58]
In the citing paper
“Examination of the crystal structure of WZ4002 in complex with EGFR T790M (14) reveals that both L718 and L844 are in direct contact with the inhibitor; L718 primarily with the aniline ring and L844 with the pyrimidine ring (Figure 2A).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“Cysteine 797 is the site of covalent binding for all three of these agents (14–16).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“They are not only more potent on EGFR T790M, but also selectively inhibit mutant over WT EGFR and hence should lead to increased clinical efficacy and less toxicity compared with afatinib (14–16).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“C797 is the site of covalent binding of WZ4002 and previously demonstrated to lead to drug resistance if mutated to serine (14).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“CO-1686 is structurally more closely related to WZ4002 than to AZD9291 and in all of the models tested CO-1686 is very similar in vitro to WZ4002 (14–16).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“However, ENU mutagenesis studies have been predictive of clinical drug resistance mutations in several prior studies (14, 24).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“In prior studies, introduction of C797S into the background of EGFR L858R/T790M or EGFR Del 19/T790M resulted in significant loss of cellular potency for WZ4002 (14).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“Analogously, a non-covalent analogue of WZ4002, WZ4003, was ineffective in in vitro models of EGFR T790M (14).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“These include the development of mutant selective EGFR kinase inhibitors, including WZ4002, CO-1686 and AZD9291, which to date have demonstrated encouraging efficacy in both preclinical models and in EGFR mutant NSCLC patients with EGFR T790M mediated drug resistance (14–18).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“WZ4002 is a covalent pyrimidine EGFR inhibitor specifically designed against EGFR T790M that is 30–100 fold more potent against EGFR T790M, and up to 100 fold less potent against wild type EGFR than quinazoline based EGFR inhibitors in vitro and is effective in murine models of lung cancer driven by EGFR T790M [84].”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [84]
In the citing paper
“Both 2G and 3G EGFR‐TKI are irreversible small‐molecule inhibitors that covalently bind to EGFR kinase by targeting the cysteine‐797 residue, located in the ATP binding pocket, and 3G EGFR‐TKI are considered to be more specific for EGFR sensitizing mutations than 2G EGFR‐TKI.12, 13, 14”
In the citing paper
“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 [43]
In the citing paper
“Standard of care is rapidly changing with the development of third-generation, mutant-selective EGFR-TKIs that have activity against cells that harbor TKI-sensitive EGFR mutations. Unlike conventional EGFR-TKIs, this activity is maintained in the presence of T790M resistance mutation.8,9”
From Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non–Small-Cell Lung Cancer (2016) · cites this paper as [9]
In the citing paper
“Next-generation EGFR TKIs have since been developed specifically to target the T790M mutation, 17,18 and they have demonstrated high and durable responses in patients with advanced EGFRmutant NSCLC who have been previously treated and in whom firstor second-generation EGFR TKIs have failed.”
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Metadata
- Authors
- Zhou, W., Ercan, D., Chen, L., Yun, C.-H., Li, D., Capelletti, M., Cortot, A. B., Chirieac, L., Iacob, R. E., Padera, R., Engen, J. R., Wong, K.-K., Eck, M. J., Gray, N. S., & Jänne, P. A.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Northeastern University (US)
- Corresponding author
- Gray, Nathanael S.
- ORCID
- Venue
- Nature
- Published
- 2009-12
- Volume
- 462
- Issue
- 7276
- Pages
- 1070-1074
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2879581
- OpenAlex
- W2133963438
- Cited by
- 1,013
- References
- 30
- Citations by year
- 2026: 32 · 2025: 43 · 2024: 39 · 2023: 60 · 2022: 46 · 2021: 55 · 2020: 62 · 2019: 55 · 2018: 66 · 2017: 84 · 2016: 82 · 2015: 75 · 2014: 71 · 2013: 82 · 2012: 54
- FWCI
- 45.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (R01AG2400401)
- National Cancer Institute (R01CA116020, R01CA122794, R01CA130876, R01CA11446, P50CA090578, R01CA135257, R01CA080942)
- National Institute of General Medical Sciences (R01GM070590)
- 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 › Protein Kinase Regulation and GTPase Signaling
- Keywords
- EGFR kinase inhibitors, mutant-selective inhibitors, irreversible kinase inhibitors, non-small cell lung cancer, drug resistance, co-crystallization, gatekeeper mutation
- MeSH terms
- Animals, Antineoplastic Agents, Drug Evaluation, Preclinical, Lung, Models, Chemical, Models, Molecular, Mutation, Phosphorylation, Drug Resistance, Neoplasm, NIH 3T3 Cells, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Mice, ErbB Receptors
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