Home LiteratureArticle Details
该文献已被撤稿（Retracted Publication），引用前请核实。
PMID: 8134396 Published · ppublish English Journal Article Retracted Publication

4,5-Dianilinophthalimide: a protein-tyrosine kinase inhibitor with selectivity for the epidermal growth factor receptor signal transduction pathway and potent in vivo antitumor activity.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 91 ·No. 6 ·1994-03-15 ·Pages 2334-8

Buchdunger E, Trinks U, Mett H, Regenass U, Müller M, Meyer T, McGlynn E, Pinna LA, Traxler P, Lydon NB

Abstract

Deregulated signal transduction via the epidermal growth factor receptor (EGF-R) family of protein-tyrosine kinase growth factor receptors is associated with proliferative diseases. We describe a class of compounds (4,5-dianilinophthalimides) that inhibit the EGF-R protein-tyrosine kinase in vitro with high selectivity. In cells, 4,5-dianilinophthalmide selectively inhibited both ligand-induced EGF-R and p185c-erbB2 autophosphorylation and c-fos mRNA induction. Antitumor activity could be demonstrated in vivo against xenografts of the A431 and SK-OV-3 tumors, which overexpress the EGF-R and p185c-erbB2, respectively. In contrast, a platelet-derived growth factor-driven tumor was not inhibited by 4,5-dianilinophthalimide, which is compatible with its cellular selectivity and hypothesized mechanism of action. No overt cumulative toxicity was observed during treatment even though high efficacy was observed, indicating a good therapeutic window. 4,5-Dianilinophthalimides may offer therapeutic agents for the treatment of hyperproliferative diseases that overexpress EGF-R family protein-tyrosine kinases or their ligands.

MeSH Terms
3T3 Cells Animals Antineoplastic Agents/pharmacology Cell Division ErbB Receptors/antagonists & inhibitors,metabolism Humans Mice Mice, Inbred BALB C Molecular Conformation Molecular Structure Phosphorylation Phthalimides/pharmacology Signal Transduction/drug effects Tumor Cells, Cultured
Chemicals
Antineoplastic Agents Phthalimides ErbB Receptors
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Buchdunger E
CIBA Pharmaceuticals Division, CIBA-Geigy Limited, Basel, Switzerland.
Trinks U
Mett H
Regenass U
Müller M
Meyer T
McGlynn E
Pinna L A
Traxler P
Lydon N B
References (39)
39 references, click to expand
  1. Potent selective inhibitors of protein kinase C.
    FEBS Lett. 1989 Dec 18;259(1):61-3 PMID: 2532156
  2. Oncogenes, growth factors, and signal transduction.
    N Engl J Med. 1989 Nov 16;321(20):1383-91 PMID: 2682241
  3. Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast.
    Cell. 1990 Jun 15;61(6):1121-35 PMID: 1693546
  4. Thiazolidine-diones. Biochemical and biological activity of a novel class of tyrosine protein kinase inhibitors.
    J Biol Chem. 1990 Dec 25;265(36):22255-61 PMID: 2176210
  5. Prevalence of aberrant expression of the epidermal growth factor receptor in human cancers.
    Br Med Bull. 1991 Jan;47(1):87-98 PMID: 1863851
  6. The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C.
    J Biol Chem. 1991 Aug 25;266(24):15771-81 PMID: 1874734
  7. Imbalanced expression of cellular nuclear oncogenes caused by v-sis/PDGF-2.
    Oncogene. 1991 Sep;6(9):1531-7 PMID: 1923519
  8. Selective effect of poly(lysine) on the enhancement of the lyn tyrosine protein kinase activity. Increased specificity toward src peptides.
    Eur J Biochem. 1992 Mar 15;204(3):1159-63 PMID: 1372554
  9. Distinctive patterns of hyperplasia in transgenic mice with mouse mammary tumor virus transforming growth factor-alpha. Characterization of mammary gland and skin proliferations.
    Am J Pathol. 1992 May;140(5):1131-46 PMID: 1316084
  10. Large-scale purification and characterisation of a recombinant epidermal growth-factor receptor protein-tyrosine kinase. Modulation of activity by multiple factors.
    Eur J Biochem. 1992 Jul 1;207(1):265-75 PMID: 1321046
  11. Monoclonal antibodies against the extracellular domain of the erbB-2 receptor function as partial ligand agonists.
    J Biol Chem. 1992 Jul 25;267(21):15160-7 PMID: 1353079
  12. Benzopyranones and benzothiopyranones: a class of tyrosine protein kinase inhibitors with selectivity for the v-abl kinase.
    Cancer Res. 1992 Aug 15;52(16):4492-8 PMID: 1643641
  13. Differential inhibition of the epidermal growth factor-, platelet-derived growth factor-, and protein kinase C-mediated signal transduction pathways by the staurosporine derivative CGP 41251.
    Cancer Res. 1992 Oct 1;52(19):5353-8 PMID: 1394140
  14. Transgenic overexpression of transforming growth factor alpha bypasses the need for c-Ha-ras mutations in mouse skin tumorigenesis.
    Mol Cell Biol. 1992 Oct;12(10):4643-53 PMID: 1406654
  15. Selective inhibition of tumor cell growth by a recombinant single-chain antibody-toxin specific for the erbB-2 receptor.
    Cancer Res. 1992 Nov 15;52(22):6310-7 PMID: 1358432
  16. Spleen protein tyrosine kinases TPK-IIB and CSK display different immunoreactivity and opposite specificities toward c-src-derived peptides.
    FEBS Lett. 1992 Nov 30;313(3):291-4 PMID: 1280230
  17. Inhibitors of protein kinase C. 3. Potent and highly selective bisindolylmaleimides by conformational restriction.
    J Med Chem. 1993 Jan 8;36(1):21-9 PMID: 8421286
  18. Amplification and overexpression of the erbB-2 gene in human tumors: its involvement in tumor development, significance as a prognostic factor, and potential as a target for cancer therapy.
    Semin Cancer Biol. 1993 Feb;4(1):19-26 PMID: 8095411
  19. A synthetic peptide substrate specific for casein kinase I.
    FEBS Lett. 1989 Dec 18;259(1):75-8 PMID: 2599114
  20. Expression and partial characterization of rat protein kinase C-delta and protein kinase C-zeta in insect cells using recombinant baculovirus.
    J Cell Biochem. 1992 Jul;49(3):239-50 PMID: 1644861
  21. Growth factor signaling by receptor tyrosine kinases.
    Neuron. 1992 Sep;9(3):383-91 PMID: 1326293
  22. In vitro cultivation of human tumors: establishment of cell lines derived from a series of solid tumors.
    J Natl Cancer Inst. 1973 Nov;51(5):1417-23 PMID: 4357758
  23. A comparison of the response of human lung carcinoma xenografts to vindesine and vincristine.
    Br J Cancer. 1982 Mar;45(3):466-8 PMID: 6280742
  24. Altered epidermal growth factor (EGF)-stimulated protein kinase activity in variant A431 cells with altered growth responses to EGF.
    Proc Natl Acad Sci U S A. 1982 Apr;79(8):2574-8 PMID: 6283535
  25. FBJ murine osteosarcoma virus: identification and molecular cloning of biologically active proviral DNA.
    J Virol. 1982 Nov;44(2):674-82 PMID: 6292525
  26. Effects of epidermal growth factor receptor concentration on tumorigenicity of A431 cells in nude mice.
    Cancer Res. 1986 Sep;46(9):4701-5 PMID: 3015393
  27. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells.
    Science. 1987 Jul 10;237(4811):178-82 PMID: 2885917
  28. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
    Anal Biochem. 1987 Apr;162(1):156-9 PMID: 2440339
  29. Expression of the c-erbB-2 protein in normal and transformed cells.
    Int J Cancer. 1987 Aug 15;40(2):246-54 PMID: 3301694
  30. Receptors for epidermal growth factor and other polypeptide mitogens.
    Annu Rev Biochem. 1987;56:881-914 PMID: 3039909
  31. Requirement for intrinsic protein tyrosine kinase in the immediate and late actions of the EGF receptor.
    Nature. 1987 Aug 27-Sep 2;328(6133):820-3 PMID: 3498122
  32. Point mutation at the ATP binding site of EGF receptor abolishes protein-tyrosine kinase activity and alters cellular routing.
    Cell. 1987 Oct 23;51(2):199-209 PMID: 3499230
  33. Epidermal-growth-factor-dependent transformation by a human EGF receptor proto-oncogene.
    Science. 1987 Dec 4;238(4832):1408-10 PMID: 3500513
  34. Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells.
    Cell. 1987 Dec 24;51(6):1063-70 PMID: 3500791
  35. Alteration of epidermal growth factor receptor activity by mutation of its primary carboxyl-terminal site of tyrosine self-phosphorylation.
    J Biol Chem. 1988 Mar 15;263(8):3610-7 PMID: 3346210
  36. Partially dephosphorylated phosphopeptide AcSer(P)-Ser(P)-Ser(P) is an excellent substrate for casein kinase-2.
    FEBS Lett. 1988 Sep 12;237(1-2):225-8 PMID: 3169237
  37. A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity.
    Int J Cancer. 1989 May 15;43(5):851-6 PMID: 2714889
  38. Overexpression of the c-erbB-2 protein in human breast tumor cell lines.
    J Cell Biochem. 1989 Feb;39(2):167-73 PMID: 2565909
  39. Synthetic peptides reproducing the EGF-receptor segment homologous to the pp60v-src phosphoacceptor site. Phosphorylation by tyrosine protein kinases.
    Biochim Biophys Acta. 1989 Jul 11;1012(2):191-5 PMID: 2500978
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.91.6.2334
Published
1994-03-15
Pages
2334-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC43365
Subset
IM
Corrections
RetractionIn
PMID: 9786782
External Links
PubMed source DOI: 10.1073/pnas.91.6.2334 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2