Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1 H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung Cancers
Abstract
Over the past decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately limit the full potential of these therapies to control mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we describe our approach toward the discovery of 47 (EGF816, nazartinib), a novel, covalent mutant-selective EGFR inhibitor with equipotent activity on both oncogenic and T790M-resistant EGFR mutations. Through molecular docking studies we converted a mutant-selective high-throughput screening hit (7) into a number of targeted covalent EGFR inhibitors with equipotent activity across mutants EGFR and good WT-EGFR selectivity. We used an abbreviated in vivo efficacy study for prioritizing compounds with good tolerability and efficacy that ultimately led to the selection of 47 as the clinical candidate.
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Nazartinib demonstrates potent inhibitory effects on pEGFR levels in H3255, HCC827, and H1975 cell lines, leading to effective inhibition of cell proliferation.
“The drug demonstrates potent inhibitory effects on pEGFR levels in H3255, HCC827, and H1975 cell lines, leading to effective inhibition of cell proliferation.173–176”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [173]
Nazartinib is a third-generation, covalent, irreversible, and highly selective inhibitor of mutant EGFR developed by Novartis.
“Nazartinib (EGF816, NVS-816) (60) is a third-generation, covalent, irreversible, and highly selective inhibitor of mutant EGFR, developed by Novartis.173”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [173]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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- Authors
- Lelais, G., Epple, R., Marsilje, T. H., Long, Y. O., McNeill, M., Chen, B., Lu, W., Anumolu, J., Badiger, S., Bursulaya, B., DiDonato, M., Fong, R., Juarez, J., Li, J., Manuia, M., Mason, D. E., Gordon, P., Groessl, T., Johnson, K., Jia, Y., Kasibhatla, S., Li, C., Isbell, J., Spraggon, G., Bender, S., & Michellys, P.-Y.
- Affiliations
- Genomics Institute of the Novartis Research Foundation (US)
- Aurigene Discovery Technologies (India) (IN)
- Corresponding author
- Lelais, Gérald
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-07-19
- Volume
- 59
- Issue
- 14
- Pages
- 6671-6689
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2476256861
- Cited by
- 95
- References
- 46
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 9 · 2023: 7 · 2022: 12 · 2021: 9 · 2020: 11 · 2019: 12 · 2018: 9 · 2017: 14 · 2016: 3
- FWCI
- 11.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- EGFR inhibitors, covalent inhibitors, T790M resistance, L858R mutation, EGFR exon 19 deletion, non-small cell lung cancer, mutant-selective inhibitors, molecular docking
- MeSH terms
- Animals, Antineoplastic Agents, Benzimidazoles, Carcinoma, Non-Small-Cell Lung, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Lung Neoplasms, Male, Mice, Inbred BALB C, Mice, Nude, Models, Molecular, Molecular Conformation, Mutation, Neoplasms, Experimental, Nicotine, Structure-Activity Relationship, Rats, Wistar, Crystallography, X-Ray, Protein Kinase Inhibitors, Cell Proliferation, Mice, Rats, Drug Discovery, ErbB Receptors
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