Cited by 95Lung Cancer Treatments and MutationsSynthesis and biological activityHER2/EGFR in Cancer Research

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

Lelais, Gérald, Epple, Robert, Marsilje, Thomas H., Long, Yun O., McNeill, Matthew, Chen, Bei, Lu, Wenshuo, Anumolu, Jaganmohan +18 more·2016·Journal of Medicinal Chemistry

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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Crossref · 10.1021/acs.jmedchem.5b01985

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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
Venue
Journal of Medicinal Chemistry
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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