Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy.
Bioorg Med Chem. 2010 Feb 15;18(4):1482-96. doi: 10.1016/j.bmc.2010.01.011. Epub 2010 Jan 11.
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.
本文描述了一系列吲哚啉-2-酮类 RET 酪氨酸激酶抑制剂的合成、构效关系（SAR）和结构数据。这些化合物的设计旨在探索 RET 活性位点内吲哚啉酮骨架周围的可用空间。对不同位置的几个取代基进行了测试，并利用生化数据绘制了一个关于立体和静电相互作用的分子模型，该模型可用于设计更有效和选择性的 RET 抑制剂。还解决了 RET 激酶结构域与三种抑制剂复合物的晶体结构。这三种化合物都结合在 ATP 口袋中，并与激酶铰链区形成两个氢键。晶体结构分析证实了分子建模的预测，并有助于完善 SAR 结果。这些数据为开发用于治疗 RET 驱动型癌症的吲哚啉酮抑制剂提供了重要信息。
