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The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity

DOI: 10.1016/j.ejmech.2016.01.039 DOI Help

Authors: Rebecca Newton (Cancer Research UK Manchester Institute) , Katherine A. Bowler (Cancer Research UK Manchester Institute) , Emily Burns (Cancer Research UK London Research Institute) , Philip J. Chapman (Cancer Research UK Manchester Institute) , Emma E. Fairweather (Cancer Research UK Manchester Institute) , Samantha J. R. Fritzl (Cancer Research UK Manchester Institute) , Kristin M. Goldberg (Cancer Research UK Manchester Institute) , Niall M. Hamilton (Cancer Research UK Manchester Institute) , Sarah V. Holt (Cancer Research UK Manchester Institute) , Gemma V. Hopkins (Cancer Research UK Manchester Institute) , Stuart D. Jones (Cancer Research UK Manchester Institute) , Allan M. Jordan (Cancer Research UK Manchester Institute) , Amanda J. Lyons (Cancer Research UK Manchester Institute) , H. Nikki March (Cancer Research UK Manchester Institute) , Neil Mcdonald (Cancer Research UK London Research Institute) , Laura A. Maguire (Cancer Research UK Manchester Institute) , Daniel P. Mould (Cancer Research UK Manchester Institute) , Andy Purkiss (Cancer Research UK London Research Institute) , Helen F. Small (Cancer Research UK Manchester Institute) , Alexandra I. J. Stowell (Cancer Research UK Manchester Institute) , Graeme J. Thomson (Cancer Research UK Manchester Institute) , Ian D. Waddell (Cancer Research UK Manchester Institute) , Bohdan Waszkowycz (Cancer Research UK Manchester Institute) , Amanda J. Watson (Cancer Research UK Manchester Institute) , Donald J. Ogilvie (Cancer Research UK Manchester Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry , VOL 112 , PAGES 20 - 32

State: Published (Approved)
Published: April 2016
Diamond Proposal Number(s): 9826

Abstract: 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.

Journal Keywords: RET; Kinase; Quinazoline

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography