Abstract | BACKGROUND: METHODS: RESULTS:
Motesanib inhibited Kit autophosphorylation in CHO cell lines expressing primary activating mutations in exon 9 (AYins503-504, IC50 = 18 nM) and exon 11 (V560 D, IC50 = 5 nM; Delta552-559, IC50 = 1 nM). Motesanib also demonstrated activity against kinase domain mutations conferring imatinib resistance (V560D/V654A, IC50 = 77 nM; V560D/T670I, IC50 = 277 nM; Y823 D, IC50 = 64 nM) but failed to inhibit the imatinib-resistant D816V mutant (IC50 > 3000 nM). Motesanib suppressed the proliferation of Ba/F3 cells expressing Kit mutants with IC50 values in good agreement with those observed in the autophosphorylation assays. CONCLUSIONS: In conclusion, our data suggest that motesanib possesses inhibitory activity against primary Kit mutations and some imatinib-resistant secondary mutations.
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Authors | Sean Caenepeel, Lisa Renshaw-Gegg, Angelo Baher, Tammy L Bush, Will Baron, Todd Juan, Raffi Manoukian, Andrew S Tasker, Anthony Polverino, Paul E Hughes |
Journal | Journal of experimental & clinical cancer research : CR
(J Exp Clin Cancer Res)
Vol. 29
Pg. 96
(Jul 15 2010)
ISSN: 1756-9966 [Electronic] England |
PMID | 20633291
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Indoles
- Oligonucleotides
- Niacinamide
- Proto-Oncogene Proteins c-kit
- imetelstat
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Topics |
- Animals
- Blotting, Western
- CHO Cells
- Cell Proliferation
- Cricetinae
- Cricetulus
- Female
- Gastrointestinal Stromal Tumors
(drug therapy, genetics, pathology)
- Humans
- Indoles
(pharmacology)
- Mice
- Mice, Inbred C57BL
- Mutation
(genetics)
- Niacinamide
(analogs & derivatives, pharmacology)
- Oligonucleotides
- Phosphorylation
- Proto-Oncogene Proteins c-kit
(antagonists & inhibitors, genetics)
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