Research paper
The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity

https://doi.org/10.1016/j.ejmech.2016.01.039Get rights and content
Under a Creative Commons license
open access

Highlights

  • Novel anilinoquinazoline RET inhibitors have been prepared.

  • Phenolic moieties display enhanced potency but decreased metabolic stability.

  • Substitution patterns adjacent to the phenol improve metabolic stability.

  • These substituents deliver unanticipated improvements in selectivity.

  • Improvements in selectivity are explained through X-ray crystallographic studies.

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.

Keywords

RET
Kinase
Quinazoline

Cited by (0)