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

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

  • Eur J Med Chem. 2016 Apr 13;112:20-32. doi: 10.1016/j.ejmech.2016.01.039.
Rebecca Newton 1,  Katherine A Bowler 2,  Emily M Burns 3,  Philip J Chapman 2,  Emma E Fairweather 2,  Samantha J R Fritzl 2,  Kristin M Goldberg 2,  Niall M Hamilton 2,  Sarah V Holt 2,  Gemma V Hopkins 2,  Stuart D Jones 2,  Allan M Jordan 2,  Amanda J Lyons 2,  H Nikki March 2,  Neil Q McDonald 4,  Laura A Maguire 2,  Daniel P Mould 2,  Andrew G Purkiss 3,  Helen F Small 2,  Alexandra I J Stowell 2,  Graeme J Thomson 2,  Ian D Waddell 2,  Bohdan Waszkowycz 2,  Amanda J Watson 2,  Donald J Ogilvie 2
Affiliations

Affiliations

  • 1 Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK. Electronic address: rebecca.newton@cruk.manchester.ac.uk.
  • 2 Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
  • 3 Structural Biology Laboratory, Cancer Research UK London Research Institute, London, WC2A 3LY, England, UK.
  • 4 Structural Biology Laboratory, Cancer Research UK London Research Institute, London, WC2A 3LY, England, UK; Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, Malet Street, London WC1E 7HX, England, UK.
PMID: 26874741 DOI: 10.1016/j.ejmech.2016.01.039
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 VEGFR2/KDR/Flk-1, 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 VEGFR2/KDR/Flk-1.

Keywords

Kinase; Quinazoline; RET.

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