5AMN

The Discovery of 2-Substituted Phenol Quinazolines as Potent and Selective RET Kinase Inhibitors

Summary for 5AMN

• Entry DOI: 10.2210/pdb5amn/pdb
• Descriptor: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET, 4-[3-HYDROXYANILINO]-6,7-DIMETHOXYQUINAZOLINE, FORMIC ACID, ... (4 entities in total)
• Functional Keywords: transferase, ret, oncogene, receptor tyrosine kinase, chemical inhibitor, cancer
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cell membrane ; Single-pass type I membrane protein : P07949
• Total number of polymer chains: 1
• Total formula weight: 34973.10

Authors

Newton, R.,Bowler, K.,Burns, E.M.,Chapman, P.,Fairweather, E.,Fritzl, S.,Goldberg, K.,Hamilton, N.M.,Holt, S.V.,Hopkins, G.V.,Jones, S.D.,Jordan, A.M.,Lyons, A.,McDonald, N.Q.,Maguire, L.A.,Mould, D.P.,Purkiss, A.G.,Small, H.F.,Stowell, A.,Thomson, G.J.,Waddell, I.D.,Waszkowycz, B.,Watson, A.J.,Ogilvie, D.J. (deposition date: 2015-03-11, release date: 2016-02-17, Last modification date: 2024-10-23)

Primary citation

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.
The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity.
Eur J Med Chem, 112:20-32, 2016

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.

PubMed: 26874741
DOI: 10.1016/j.ejmech.2016.01.039

Experimental method

X-RAY DIFFRACTION (2.57 Å)