The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity.
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
Maguire, Laura A
Mould, Daniel P
Small, Helen F
Stowell, Alexandra I J
Thomson, Graeme J
Waddell, Ian D
Watson, Amanda J
Ogilvie, Donald J
AffiliationCancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX
MetadataShow full item record
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.
CitationThe discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity. 2016, 112:20-32 Eur J Med Chem
JournalEuropean Journal of Medicinal Chemistry
- Anilinoquinazoline inhibitors of the RET kinase domain-Elaboration of the 7-position.
- Authors: Jordan AM, Begum H, Fairweather E, Fritzl S, Goldberg K, Hopkins GV, Hamilton NM, Lyons AJ, March HN, Newton R, Small HF, Vishwanath S, Waddell ID, Waszkowycz B, Watson AJ, Ogilvie DJ
- Issue date: 2016 Jun 1
- High Affinity Pharmacological Profiling of Dual Inhibitors Targeting RET and VEGFR2 in Inhibition of Kinase and Angiogeneis Events in Medullary Thyroid Carcinoma.
- Authors: Dunna NR, Kandula V, Girdhar A, Pudutha A, Hussain T, Bandaru S, Nayarisseri A
- Issue date: 2015
- A Pyrazolo[3,4-d]pyrimidin-4-amine Derivative Containing an Isoxazole Moiety Is a Selective and Potent Inhibitor of RET Gatekeeper Mutants.
- Authors: Yoon H, Kwak Y, Choi S, Cho H, Kim ND, Sim T
- Issue date: 2016 Jan 14
- Vandetanib as a potential new treatment for estrogen receptor-negative breast cancers.
- Authors: Hatem R, Labiod D, Château-Joubert S, de Plater L, El Botty R, Vacher S, Bonin F, Servely JL, Dieras V, Bièche I, Marangoni E
- Issue date: 2016 May 15
- A transplantable human medullary thyroid carcinoma as a model for RET tyrosine kinase-driven tumorigenesis.
- Authors: Johanson V, Ahlman H, Bernhardt P, Jansson S, Kölby L, Persson F, Stenman G, Swärd C, Wängberg B, Stridsberg M, Nilsson O
- Issue date: 2007 Jun