The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity
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Updated: Mar 25, 2026
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Rebecca Newton1, Katherine A Bowler1, Emily M Burns2
1Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, England, UK.
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.
Insights
Researchers developed a potent and selective RET kinase inhibitor to treat cancers like medullary thyroid cancer. This new compound, 36, shows improved safety by avoiding inhibition of KDR, a common cause of toxicity in other drugs.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- Receptor tyrosine kinase RET deregulation is linked to various cancers, including medullary thyroid cancer.
- Existing multi-kinase inhibitors targeting RET often inhibit KDR, causing dose-limiting toxicities.
- There is a clinical need for selective RET kinase inhibitors with improved safety profiles.
Purpose of the Study:
- To identify a potent and selective RET kinase inhibitor.
- To address the toxicities associated with non-selective kinase inhibitors.
- To use structure-based drug design starting from vandetanib.
Main Methods:
- Structure-based drug design was employed.
- Phenolic anilinoquinazolines were synthesized and evaluated.
- Metabolic stability and kinase selectivity were assessed.
- Lead optimization focused on mitigating metabolic liabilities and enhancing selectivity.
Main Results:
- Initial compounds showed improved RET affinity but high metabolic clearance.
- A flanking substituent was introduced to improve hepatocyte stability.
- This modification also significantly enhanced selectivity against KDR.
- Compound 36 emerged as a potent RET inhibitor with superior selectivity.
Conclusions:
- A novel, potent, and selective RET inhibitor (36) was identified.
- The structural modifications successfully addressed metabolic instability and off-target KDR inhibition.
- This discovery offers a promising therapeutic candidate for RET-driven cancers with potentially reduced toxicity.
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