Newton, R. and Bowler, K.A. and Burns, E.M. and Chapman, P.J. and Fairweather, E.E. and Fritzl, S.J.R. and Goldberg, K.M. and Hamilton, N.M. and Holt, S.V. and Hopkins, G.V. and Jones, S.D. and Jordan, A.M. and Lyons, A.J. and Nikki March, H. and McDonald, Neil Q. and Maguire, L.A. and Mould, D.P. and Purkiss, A.G. and Small, H.F. and Stowell, A.I.J. and Thomson, G.J. and Waddell, I.D. and Waszkowycz, B. and Watson, A.J. and Ogilvie, D.J. (2016) The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity. European Journal of Medicinal Chemistry 112 , pp. 20-32. ISSN 0223-5234.
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.
Metadata
| Item Type: | Article |
|---|---|
| Keyword(s) / Subject(s): | Kinase, Quinazoline, RET |
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Research Centres and Institutes: | Structural Molecular Biology, Institute of (ISMB) |
| Depositing User: | Administrator |
| Date Deposited: | 01 Mar 2016 12:14 |
| Last Modified: | 02 Aug 2023 17:22 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/14530 |
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