Targeting the KIT activating switch control pocket: a novel mechanism to inhibit neoplastic mast cell proliferation and mast cell activation
| Autor: | Dean D. Metcalfe, E Ching Chan, Alasdair M. Gilfillan, D L Flynn, Olga Simakova, Todd M. Wilson, S N Bandara, Yun Bai, Geethani Bandara, W.P. Lu, Irina Maric, Scott C. Wise |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Stem cell factor Article Receptor tyrosine kinase tyrosine kinase inhibitor Mastocytosis Systemic medicine Animals Humans Mast Cells Systemic mastocytosis Protein Kinase Inhibitors Cell Proliferation mastocytosis biology Cell growth HEK 293 cells Degranulation KIT Hematology Mast cell medicine.disease Proto-Oncogene Proteins c-kit medicine.anatomical_structure Oncology Immunology biology.protein Cancer research switch pocket mast cell KIT D816V |
| Zdroj: | Leukemia |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/leu.2012.218 |
| Popis: | Activating mutations in the receptor tyrosine kinase KIT, most notably KIT D816V, are commonly observed in patients with systemic mastocytosis. Thus, inhibition of KIT has been a major focus for treatment of this disorder. Here we investigated a novel approach to such inhibition. Utilizing rational drug design, we targeted the switch pocket (SP) of KIT, which regulates its catalytic conformation. Two SP inhibitors thus identified, DP-2976 and DP-4851, were examined for effects on neoplastic mast cell proliferation and mast cell activation. Autophosphorylation of both wild-type and, where also examined, KIT D816V activation was blocked by these compounds in transfected 293T cells, HMC 1.1 and 1.2 human mast cell lines, and in CD34(+)-derived human mast cells activated by stem cell factor (SCF). Both inhibitors induced apoptosis in the neoplastic mast cell lines and reduced survival of primary bone marrow mast cells from patients with mastocytosis. Moreover, the SP inhibitors more selectively blocked SCF potentiation of FcɛRI-mediated degranulation. Overall, SP inhibitors represent an innovative mechanism of KIT inhibition whose dual suppression of KIT D816V neoplastic mast cell proliferation and SCF-enhanced mast cell activation may provide significant therapeutic benefits. |
| Databáze: | OpenAIRE |
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