Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors
| Autor: | May B. Chien, Julie M. Cherrington, Dirk B. Mendel, Narmada Shenoy, Cheryl A. London, Albert Taiching Liao, Gerald McMahon |
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| Rok vydání: | 2002 |
| Předmět: |
Indoles
Cell Survival Poly ADP ribose polymerase Immunology Mutant Mast-Cell Sarcoma Antineoplastic Agents Apoptosis Biology Proto-Oncogene Mas Biochemistry Receptor tyrosine kinase Dogs Tumor Cells Cultured Animals Pyrroles Enzyme Inhibitors Phosphorylation chemistry.chemical_classification Dose-Response Relationship Drug Point mutation Autophosphorylation Cell Biology Hematology Protein-Tyrosine Kinases Molecular biology Protein Structure Tertiary Proto-Oncogene Proteins c-kit Enzyme chemistry Mutation biology.protein Tyrosine kinase Platelet-derived growth factor receptor |
| Zdroj: | Blood. 100:585-593 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2001-12-0350 |
| Popis: | Mutations in the proto-oncogene c-kit, including point mutations, deletions, or duplications in the negative regulatory juxtamembrane (JM) domain or point mutations in the catalytic domain, have been observed in human and canine cancers and often result in constitutive activation of Kit in the absence of ligand binding. To identify a receptor tyrosine kinase (RTK) inhibitor capable of blocking the function of mutant Kit, we evaluated 3 indolinones (SU11652, SU11654, and SU11655) that act as competitive inhibitors of adenosine triphosphate binding to several members of the split kinase family of RTKs, including VEGFR, FGFR, PDGFR, and Kit. Mast cell lines expressing either wild-type (WT) Kit, a point mutation in the JM domain, a tandem duplication in the JM domain, or a point mutation in the catalytic domain were used for these studies. All 3 indolinones inhibited phosphorylation of WT Kit in the presence of stem cell factor at concentrations as low as 0.01 μM. Autophosphorylation of both JM mutants was inhibited at 0.01 to 0.1 μM, resulting in cell cycle arrest within 24 hours, whereas autophosphorylation of the catalytic domain mutant was inhibited at 0.25 to 0.5 μM, resulting in cell death within 24 hours. poly(ADP-ribose) polymerase (PARP) cleavage was noted in all Kit mutant lines after indolinone treatment. In summary, SU11652, SU11654, and SU11655 are effective RTK inhibitors capable of disrupting the function of all forms of mutant Kit. Because the concentrations of drug necessary for receptor inhibition are readily achievable and nontoxic in vivo, these compounds may be useful in the treatment of spontaneous cancers expressing Kit mutations. |
| Databáze: | OpenAIRE |
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