The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivityMore about Open Access at the Crick
Authors listRebecca Newton Katherine A Bowler Emily M Burns Philip J Chapman Emma E Fairweather Samantha JR Fritzl Kristin M Goldberg Niall M Hamilton Sarah V Holt Gemma V Hopkins Stuart D Jones Allan M Jordan Amanda J Lyons H Nikki March Neil McDonald Laura A Maguire Daniel P Mould Andrew G Purkiss Helen F Small Alexandra IJ Stowell Graeme J Thomson Ian D Waddell Bohdan Waszkowycz Amanda J Watson Donald J Ogilvie
Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.