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J Med Chem. 2005 Oct 6;48(20):6194-201.

Molecular modeling of wild-type and D816V c-Kit inhibition based on ATP-competitive binding of ellipticine derivatives to tyrosine kinases.

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  • 1CNRS UMR-8113, Laboratoire de Biotechnologies et Pharmacologie génétique Appliquée (LBPA) Ecole Normale Supérieure de Cachan, 61 avenue du Président Wilson, 94235 Cachan, France.


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.

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