Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis.

Abstract	Mastocytosis is associated with an activating mutation in the KIT oncoprotein (KITD816V) that results in autophosphorylation of the KIT receptor in a ligand-independent manner. This mutation is inherently resistant to imatinib and, to date, there remains no effective curative therapy for systemic mastocytosis associated with KITD816V. Dasatinib (BMS-354825) is a novel orally bioavailable SRC/ABL inhibitor that has activity against multiple imatinib-resistant BCR-ABL isoforms in vitro that is presently showing considerable promise in early-phase clinical trials of chronic myeloid leukemia (CML). Pharmacokinetic analysis suggests that high nanomolar concentrations of dasatinib can be achieved safely in humans. In this study, we demonstrate significant inhibitory activity of dasatinib against both wild-type KIT and the KITD816V mutation in the nanomolar range in in vitro and cell-based kinase assays. Additionally, dasatinib leads to growth inhibition of a KITD816V-harboring human masto-cytosis cell line. Significantly, dasatinib selectively kills primary neoplastic bone marrow mast cells from patients with systemic mastocytosis while sparing other hematopoietic cells. Computer modeling suggests that the KITD816V mutation destabilizes the inactive conformation of the KIT activation loop to which imatinib binds, but it is not predicted to impair binding of KIT by dasatinib. Based upon our results, further evaluation of dasatinib for the treatment of systemic masto-cytosis in clinical trials is warranted. Moreover, dasatinib may be of clinical utility in other disease settings driven by activating KIT mutations.
Authors	Neil P Shah, Francis Y Lee, Roger Luo, Yibin Jiang, Marjolein Donker, Cem Akin
Journal	Blood (Blood) Vol. 108 Issue 1 Pg. 286-91 (Jul 01 2006) ISSN: 0006-4971 [Print] United States
PMID	16434489 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Benzamides Ligands Piperazines Protein Kinase Inhibitors Pyrimidines Thiazoles Imatinib Mesylate Protein-Tyrosine Kinases Proto-Oncogene Proteins c-kit Dasatinib
Topics	Animals Benzamides Binding Sites Case-Control Studies Cell Line, Tumor Cell Proliferation (drug effects) Computer Simulation Dasatinib Drug Resistance, Neoplasm (genetics) Humans Imatinib Mesylate Ligands Mastocytosis, Systemic (genetics) Mice Models, Molecular Mutation Piperazines (chemistry, pharmacology) Protein Conformation Protein Kinase Inhibitors (chemistry, pharmacology) Protein Structure, Tertiary Protein-Tyrosine Kinases (antagonists & inhibitors) Proto-Oncogene Proteins c-kit (chemistry, drug effects) Pyrimidines (chemistry, pharmacology) Structure-Activity Relationship Thiazoles (chemistry, pharmacology)

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