title: Molecular modeling of wild-type and D816V c-Kit inhibition based on ATP-competitive binding of ellipticine derivatives to tyrosine kinases.
abstract: The D816V activating mutation of the c-Kit kinase domain often causes human mastocytosis. Although inhibitors of wild-type c-Kit are known (e.g. STI-571), they are at least 10 times less active against the c-Kit mutant. Several derivatives of ellipticine (5,11-dimethyl-6H-pyrido[3,4-b]carbazole), substituted at positions 1, 2, 9, and 11, were found to inhibit purified D816V and wild-type c-Kit kinase domains with comparable potencies by competing with ATP binding. We investigated the difference between these inhibitors by modeling the D816V mutation in crystal structures of inactive and active c-Kit. Molecular dynamics simulations strongly suggested that the D816V point mutation shifts the conformational equilibrium of c-Kit kinase domain toward the active conformation. All ellipticine compounds were subsequently docked to the D816V mutant c-Kit model. The model provides possible explanations for the structure-activity relationships observed among ellipticine compounds, resulting in new insights into D816V c-Kit mutant inhibition.
authors.affiliation: CNRS UMR-8113, Laboratoire de Biotechnologies et Pharmacologie génétique Appliquée (LBPA) Ecole Normale Supérieure de Cachan, 61 avenue du Président Wilson, 94235 Cachan, France.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Vendôme
authors.forename: Sébastien
authors.initials: S
authors.lastname: Letard
authors.forename: Frédéric
authors.initials: F
authors.lastname: Martin
authors.forename: Fedor
authors.initials: F
authors.lastname: Svinarchuk
authors.forename: Patrice
authors.initials: P
authors.lastname: Dubreuil
authors.forename: Christian
authors.initials: C
authors.lastname: Auclair
authors.forename: Marc
authors.initials: M
authors.lastname: Le Bret
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry*; D001667:Binding, Competitive; D004611:Ellipticines / Q000737:chemistry*; D009154:Mutation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry* / Q000235:genetics
chemical_list: D004611:Ellipticines; D047428:Protein Kinase Inhibitors; C034192:ellipticine; D000255:Adenosine Triphosphate; D019009:Proto-Oncogene Proteins c-kit