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The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity.
Newton, Rebecca Bowler, K Burns, E Chapman, Philip J Fairweather, Emma E Fritzl, Samantha J R Goldberg, Kristin M Hamilton, Niall M Holt, Sarah V Hopkins, Gemma V
Newton, Rebecca
Bowler, K
Burns, E
Chapman, Philip J
Fairweather, Emma E
Fritzl, Samantha J R
Goldberg, Kristin M
Hamilton, Niall M
Holt, Sarah V
Hopkins, Gemma V
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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.
Authors
Newton, Rebecca
Bowler, K
Burns, E
Chapman, Philip J
Fairweather, Emma E
Fritzl, Samantha J R
Goldberg, Kristin M
Hamilton, Niall M
Holt, Sarah V
Hopkins, Gemma V
Jones, Stuart D
Jordan, Allan M
Lyons, Amanda J
March, H Nikki
McDonald, N
Maguire, Laura A
Mould, Daniel P
Purkiss, A
Small, Helen F
Stowell, Alexandra I J
Thomson, Graeme J
Waddell, Ian D
Waszkowycz, Bohdan
Watson, Amanda J
Ogilvie, Donald J
Bowler, K
Burns, E
Chapman, Philip J
Fairweather, Emma E
Fritzl, Samantha J R
Goldberg, Kristin M
Hamilton, Niall M
Holt, Sarah V
Hopkins, Gemma V
Jones, Stuart D
Jordan, Allan M
Lyons, Amanda J
March, H Nikki
McDonald, N
Maguire, Laura A
Mould, Daniel P
Purkiss, A
Small, Helen F
Stowell, Alexandra I J
Thomson, Graeme J
Waddell, Ian D
Waszkowycz, Bohdan
Watson, Amanda J
Ogilvie, Donald J
Description
Date
2016-04-13
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Keywords
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Article
Citation
The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity. 2016, 112:20-32 Eur J Med Chem