Download MendeleyThe discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity.
Newton, R., Bowler, K.A., Burns, E.M., Chapman, P.J., Fairweather, E.E., Fritzl, S.J.R., Goldberg, K.M., Hamilton, N.M., Holt, S.V., Hopkins, G.V., Jones, S.D., Jordan, A.M., Lyons, A.J., Nikki March, H., McDonald, N.Q., Maguire, L.A., Mould, D.P., Purkiss, A.G., Small, H.F., Stowell, A.I.J., Thomson, G.J., Waddell, I.D., Waszkowycz, B., Watson, A.J., Ogilvie, D.J.(2016) Eur J Med Chem 112: 20-32
- PubMed: 26874741
- DOI: https://doi.org/10.1016/j.ejmech.2016.01.039
- Primary Citation of Related Structures:
5AMN - PubMed 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.
Organizational Affiliation:
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.
