Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors
Authors list
Luca Mologni Roberta Rostagno Stefania Brussolo Phillip P Knowles Svend Kjaer Judith Murray-Rust Enrico Rosso Alfonso Zambon Leonardo Scapozza Neil McDonald Vittorio Lucchini Carlo Gambacorti-PasseriniAbstract
The synthesis, structure-activity relationships (SAR) and structural data of a series of indolin-2-one inhibitors of RET tyrosine kinase are described. These compounds were designed to explore the available space around the indolinone scaffold within RET active site. Several substitutions at different positions were tested and biochemical data were used to draw a molecular model of steric and electrostatic interactions, which can be applied to design more potent and selective RET inhibitors. The crystal structures of RET kinase domain in complex with three inhibitors were solved. All three compounds bound in the ATP pocket and formed two hydrogen bonds with the kinase hinge region. Crystallographic analysis confirmed predictions from molecular modelling and helped refine SAR results. These data provide important information for the development of indolinone inhibitors for the treatment of RET-driven cancers.
Journal details
Journal Bioorganic & Medicinal Chemistry
Volume 18
Issue number 4
Pages 1482-1496
Publication date
Full text links
Publisher website (DOI) 10.1016/j.bmc.2010.01.011
Europe PubMed Central 20117004
Pubmed 20117004
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