title: Indolinone derivatives inhibit constitutively activated KIT mutants and kill neoplastic mast cells.
abstract: Mastocytosis is a neoplastic disease caused at least in part by somatic mutations of the c-KIT proto-oncogene resulting in constitutive activation of its protein product, KIT, the receptor tyrosine kinase for stem cell factor. KIT stimulates mast cell proliferation and prevents apoptosis of neoplastic mast cells. To develop potential therapies for mastocytosis we used indolinones, small molecules that inhibit tyrosine kinases. Four indolinone derivatives (SU4984, SU6663, SU6577, and SU5614) inhibited wild-type KIT, but variably inhibited constitutively activated KIT mutants. SU4984, SU6577, and SU5614 were effective against KIT with juxtamembrane activating mutations, whereas only SU6577 could suppress KIT containing either juxtamembrane or kinase domain activating mutations. Furthermore, SU4984, SU6577, and SU5614 killed neoplastic mast cells expressing a juxtamembrane-mutated KIT, whereas SU4984 and SU6577 killed neoplastic mast cells expressing KIT bearing a kinase domain mutation. These data show a direct correlation between inhibition of constitutively activated KIT and the death of neoplastic mast cells, and point to specific tyrosine kinase inhibitors as a potential therapy aimed directly at a cause of mastocytosis.
authors.affiliation: Departments of Dermatology and Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.forename: E
authors.initials: E
authors.lastname: Carter
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: C
authors.initials: C
authors.lastname: Shu
authors.forename: G
authors.initials: G
authors.lastname: McMahon
authors.forename: B J
authors.initials: BJ
authors.lastname: Longley
mesh_terms: D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008407:Mast Cells / Q000187:drug effects*; D009154:Mutation; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D007211:Indoles; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit