The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity
journal contributionposted on 2020-09-07, 11:24 authored by Rebecca 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 Q 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.
KinaseQuinazolineRETAnimalsCell LineDrug DesignHumansMiceMolecular Docking SimulationPiperidinesProtein Kinase InhibitorsProto-Oncogene Proteins c-retQuinazolinesMcDonald FC001115SBMedicinal & Biomolecular Chemistry0304 Medicinal and Biomolecular Chemistry1115 Pharmacology and Pharmaceutical Sciences0305 Organic Chemistry