Irreversible inhibition of epidermal growth factor receptor tyrosine kinase with In Vivo activity by N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (CL-387,785)

Discafani, Carolyn M.; Carroll, Marion L.; Floyd, M.Brawner; Hollander, Irwin J.; Husain, Zaheed; Johnson, Bernard D.; Kitchen, Douglas; May, Michael K.; Malo, Madhu S.; Minnick, Albert A.; Nilakantan, Ramaswamy; Shen, Ru; Wang, Yu-Fen; Wissner, Allan; Greenberger, Lee M.

doi:10.1016/s0006-2952(98)00356-6

Cited by 112HER2/EGFR in Cancer ResearchQuinazolinone synthesis and applicationsLung Cancer Treatments and Mutations

Irreversible inhibition of epidermal growth factor receptor tyrosine kinase with In Vivo activity by N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (CL-387,785)

Discafani, Carolyn M., Carroll, Marion L., Floyd, M.Brawner, Hollander, Irwin J., Husain, Zaheed, Johnson, Bernard D., Kitchen, Douglas, May, Michael K. +7 more·1999·Biochemical Pharmacology

DOI 10.1016/s0006-2952(98)00356-6

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Abstract

It has been shown previously that 4-anilino quinazolines compete with the ability of ATP to bind the epidermal growth factor receptor (EGF-R), inhibit EGF-stimulated autophosphorylation of tyrosine residues in EGF-R, and block EGF-mediated growth. Since millimolar concentrations of ATP in cells could reduce the efficacy of 4-anilino quinazolines in cells and the activity of these compounds would not be sustained once they were removed from the body, we reasoned that irreversible inhibitors of EGF-R might improve the activity of this series of compounds in animals. Molecular modeling of the EGF-R kinase domain was used to design irreversible inhibitors. We herein describe one such inhibitor: N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]2-butynamide, known as CL-387,785. This compound covalently bound to EGF-R. It also specifically inhibited kinase activity of the protein (IC50 = 370+/-120 pM), blocked EGF-stimulated autophosphorylation of the receptor in cells (ic50 approximately 5 nM), inhibited cell proliferation (IC50 = 31-125 nM) primarily in a cytostatic manner in cell lines that overexpress EGF-R or c-erbB-2, and profoundly blocked the growth of a tumor that overexpresses EGF-R in nude mice (when given orally at 80 mg/kg/day for 10 days, daily). We conclude that CL-387,785 is useful for studying the interaction of small molecules with EGF-R and may have clinical utility.

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Authors: Discafani, C. M., Carroll, M. L., Floyd, M. B., Hollander, I. J., Husain, Z., Johnson, B. D., Kitchen, D., May, M. K., Malo, M. S., Minnick, A. A., Nilakantan, R., Shen, R., Wang, Y.-F., Wissner, A., & Greenberger, L. M.
Affiliations: Wyeth (US)
Corresponding author: Greenberger, Lee M.
ORCID: Kitchen, Douglas
Malo, Madhu S.
Greenberger, Lee M.
Venue: Biochemical Pharmacology
Publisher: Elsevier BV
Published: 1999-04
Volume: 57
Issue: 8
Pages: 917-925
ISSN: 0006-2952 (ISSN-L)
DOI: 10.1016/s0006-2952(98)00356-6
OpenAlex: W1972132555
Cited by: 112
References: 30
Citations by year: 2026: 2 · 2025: 1 · 2024: 2 · 2023: 8 · 2021: 1 · 2019: 1 · 2018: 3 · 2017: 4 · 2016: 5 · 2015: 3 · 2014: 3 · 2012: 3
FWCI: 2.73
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biochemical Pharmacology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Physical Sciences › Chemistry › Organic Chemistry › Quinazolinone synthesis and applications
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords: epidermal growth factor receptor, tyrosine kinase inhibitors, irreversible inhibition, 4-anilinoquinazolines, covalent binding, c-erbB-2, cell proliferation inhibition, tumor growth inhibition, oral antitumor activity
MeSH terms: Animals, Antineoplastic Agents, Cell Cycle, Cell Division, Drug Screening Assays, Antitumor, Enzyme Inhibitors, Female, Mice, Nude, Models, Molecular, Neoplasm Transplantation, Neoplasms, Experimental, Phosphorylation, Quinazolines, Tumor Cells, Cultured, Mice, ErbB Receptors

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Irreversible inhibition of epidermal growth factor receptor tyrosine kinase with In Vivo activity by N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (CL-387,785)

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