Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors

Bioorganic & Medicinal Chemistry
Luca MologniCarlo Gambacorti-Passerini

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.

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Citations

May 9, 2012·Journal of Medicinal Chemistry·Peter DinérMorten Grøtli
Aug 4, 2012·The Journal of Biological Chemistry·Christopher C ValleyJonathan N Sachs
May 31, 2012·Human Mutation·Chou Hung SimHeung-Chin Cheng
Jun 2, 2012·Journal of Enzyme Inhibition and Medicinal Chemistry·Nadia G KandileNashwa A Ahmed
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Mar 26, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hafiz Mansoor IkramHawa Ze Jaafar
Nov 17, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lin TangLin Wang
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Jan 1, 2013·Medicinal Chemistry Research : an International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents·Subhas S KarkiJan Balzarini
Nov 28, 2020·Future Medicinal Chemistry·Cong-Cong JiaZhao-Peng Liu
Mar 24, 2012·The Journal of Organic Chemistry·Bartolo GabrieleBrunella Maria Aresta

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