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dc.contributor.authorNewton, Rebecca
dc.contributor.authorBowler, K
dc.contributor.authorBurns, E
dc.contributor.authorChapman, Philip J
dc.contributor.authorFairweather, Emma E
dc.contributor.authorFritzl, Samantha J R
dc.contributor.authorGoldberg, Kristin M
dc.contributor.authorHamilton, Niall M
dc.contributor.authorHolt, Sarah V
dc.contributor.authorHopkins, Gemma V
dc.contributor.authorJones, Stuart D
dc.contributor.authorJordan, Allan M
dc.contributor.authorLyons, Amanda J
dc.contributor.authorMarch, H Nikki
dc.contributor.authorMcDonald, N
dc.contributor.authorMaguire, Laura A
dc.contributor.authorMould, Daniel P
dc.contributor.authorPurkiss, A
dc.contributor.authorSmall, Helen F
dc.contributor.authorStowell, Alexandra I J
dc.contributor.authorThomson, Graeme J
dc.contributor.authorWaddell, Ian D
dc.contributor.authorWaszkowycz, Bohdan
dc.contributor.authorWatson, Amanda J
dc.contributor.authorOgilvie, Donald J
dc.date.accessioned2016-04-01T10:06:52Zen
dc.date.available2016-04-01T10:06:52Zen
dc.date.issued2016-04-13en
dc.identifier.citationThe discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity. 2016, 112:20-32 Eur J Med Chemen
dc.identifier.issn1768-3254en
dc.identifier.pmid26874741en
dc.identifier.doi10.1016/j.ejmech.2016.01.039en
dc.identifier.urihttp://hdl.handle.net/10541/604149en
dc.description.abstractDeregulation 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.
dc.language.isoenen
dc.rightsArchived with thanks to European journal of medicinal chemistryen
dc.titleThe discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BXen
dc.identifier.journalEuropean Journal of Medicinal Chemistryen
html.description.abstractDeregulation 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.


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