Indolinone derivatives inhibit constitutively activated KIT mutants and kill neoplastic mast cells

Mastocytosis is a neoplastic disease caused at least in part by somatic mut ations of the c-KIT protooncogene resulting in constitutive activation of i ts protein product, KIT, the receptor tyrosine kinase for stem cell factor. KIT stimulates mast cell proliferation and prevents apoptosis of neoplasti c mast cells, To develop potential therapies for mastocytosis we used indol inones, small molecules that inhibit tyrosine kinases, Four indolinone deri vatives (SU4984, SU6663, SU6577, and SU5614) inhibited wild-type KIT, but v ariably 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, where as SU4984 and SU6577 killed neoplastic mast cells expressing KIT bearing a kinase domain mutation. These data show a direct correlation between inhibi tion of constitutively activated KIT and the death of neoplastic mast cells , and point to specific tyrosine kinase inhibitors as a potential therapy a imed directly at a cause of mastocytosis.