New aminopyrimidine derivatives as inhibitors of the TAM family

In this study, we describe the synthesis of new pyrimidine analogs of BMS-777607, a potent and selective inhibitor of Met kinase. Inhibition of Met and Axl remained high whereas inhibition of Tyro3 and Mer decreased to some extend. The preferential moderate inhibition of the non-phosphorylated form of Abl1 of some derivatives suggests that they behave as type II inhibitors. This hypothesis was confirmed by docking studies into the structure of Met (3F82) and in a Tyro3 model where key interactions with the hinge region, the DFG-out motif and the allosteric pocket explain this inhibition. [Display omitted] •Novel pyrimidine-based Met inhibitors were designed and synthesized.•They inhibited potently Met and Axl, as well as Tyro3 and Mer to a lesser extend.•Molecular modeling in Met (3F82 in pdb) and in a Tyro3 model suggested a type II inhibition.