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Eur J Med Chem. 2016 Apr 13;112:20-32. doi: 10.1016/j.ejmech.2016.01.039. Epub 2016 Jan 29.

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

Author information

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.

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.

KEYWORDS:

Kinase; Quinazoline; RET

PMID:
26874741
PMCID:
PMC4896931
DOI:
10.1016/j.ejmech.2016.01.039
[Indexed for MEDLINE]
Free PMC Article

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