title: Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors.
abstract: 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.
authors.affiliation: Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy. luca.mologni@unimib.it
authors.forename: Luca
authors.initials: L
authors.lastname: Mologni
authors.forename: Roberta
authors.initials: R
authors.lastname: Rostagno
authors.forename: Stefania
authors.initials: S
authors.lastname: Brussolo
authors.forename: Phillip P
authors.initials: PP
authors.lastname: Knowles
authors.forename: Svend
authors.initials: S
authors.lastname: Kjaer
authors.forename: Judith
authors.initials: J
authors.lastname: Murray-Rust
authors.forename: Enrico
authors.initials: E
authors.lastname: Rosso
authors.forename: Alfonso
authors.initials: A
authors.lastname: Zambon
authors.forename: Leonardo
authors.initials: L
authors.lastname: Scapozza
authors.forename: Neil Q
authors.initials: NQ
authors.lastname: McDonald
authors.forename: Vittorio
authors.initials: V
authors.lastname: Lucchini
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
mesh_terms: D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D011994:Recombinant Proteins; D051096:Proto-Oncogene Proteins c-ret