title: New approaches to therapy for mastocytosis. A case for treatment with kit kinase inhibitors.
abstract: Some forms of mastocytosis are caused by c-kit mutations which cause constitutive activation of kit kinase. Compounds that inhibit kit kinase, such as indolinones, are therefore attractive as potential therapeutic agents. A hierarchy exists in the ability of compounds to inhibit kit kinase effectively. Some compounds can inhibit ligand-induced activation of wild-type receptor but are ineffective against constitutively activated mutants. Other compounds can inhibit ligand-induced activation of wild-type kit and ligand-independent activation by juxtamembrane domain mutations but not activation by activation loop mutations. Still others effectively inhibit wild-type kit and constitutively activated kit bearing either juxtamembrane or kinase domain mutations and kill the neoplastic mast cells expressing these mutants. No therapy currently exists that specifically targets a cause of mastocytosis, but there are good reasons to believe that kit kinase inhibitors may fulfill that role someday.
authors.affiliation: Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, New York, USA. j1691@columbia.edu
authors.forename: B J
authors.initials: BJ
authors.lastname: Longley
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.forename: E
authors.initials: E
authors.lastname: Carter
authors.forename: G
authors.initials: G
authors.lastname: McMahon
mesh_terms: D019943:Amino Acid Substitution; D003131:Combined Modality Therapy; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005240:Feasibility Studies; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008024:Ligands; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology*; D008415:Mastocytosis / Q000188:drug therapy* / Q000201:enzymology / Q000628:therapy; D010879:Piperazines / Q000627:therapeutic use; D017354:Point Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011519:Proto-Oncogenes; D011758:Pyrroles / Q000627:therapeutic use; D019089:Stem Cell Factor / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008024:Ligands; D010879:Piperazines; D011758:Pyrroles; C105687:SU 4984; C105686:SU 5402; C416849:SU 5614; C416850:SU 6577; C416851:SU 6663; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit