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Updated: Mar 17, 2026
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Identification of selective inhibitors of RET and comparison with current clinical candidates through development and
Amanda J Watson1, Gemma V Hopkins1, Samantha Hitchin1
1Cancer Research UK Manchester Institute, Drug Discovery Unit, University of Manchester, Manchester, M20 4BX, UK.
Abstract:
RET (REarranged during Transfection) is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activating somatic mutations are prevalent. At present, there are no known specific RET inhibitors in clinical development, although many potent inhibitors of RET have been opportunistically identified through selectivity profiling of compounds initially designed to target other tyrosine kinases. Vandetanib and cabozantinib, both multi-kinase inhibitors with RET activity, are approved for use in medullary thyroid carcinoma, but additional pharmacological activities, most notably inhibition of vascular endothelial growth factor - VEGFR2 (KDR), lead to dose-limiting toxicity. The recent identification of RET fusions present in ~1% of lung adenocarcinoma patients has renewed interest in the identification and development of more selective RET inhibitors lacking the toxicities associated with the current treatments. In an earlier publication [Newton et al, 2016; 1] we reported the discovery of a series of 2-substituted phenol quinazolines as potent and selective RET kinase inhibitors. Here we describe the development of the robust screening cascade which allowed the identification and advancement of this chemical series. Furthermore we have profiled a panel of RET-active clinical compounds both to validate the cascade and to confirm that none display a RET-selective target profile.
Insights
Researchers developed a screening cascade to identify selective RET kinase inhibitors. This approach advanced a chemical series of 2-substituted phenol quinazolines, offering potential new treatments for cancers driven by RET alterations.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The REarranged during Transfection (RET) receptor tyrosine kinase is crucial for cell functions but its aberrant activation drives oncogenesis, particularly in medullary thyroid carcinoma.
- Current treatments like vandetanib and cabozantinib inhibit RET but also VEGFR2, leading to dose-limiting toxicities.
- The discovery of RET fusions in lung adenocarcinoma necessitates the development of more selective RET inhibitors.
Purpose of the Study:
- To describe the development of a robust screening cascade for identifying selective RET kinase inhibitors.
- To validate the screening cascade using known RET-active clinical compounds.
- To advance a chemical series of 2-substituted phenol quinazolines as potent and selective RET inhibitors.
Main Methods:
- Development and implementation of a multi-step screening cascade for kinase inhibitor profiling.
- Selectivity profiling of identified RET inhibitors against a panel of kinases.
- Characterization of RET-active clinical compounds to assess their target selectivity profiles.
Main Results:
- A robust screening cascade was successfully developed and utilized.
- The cascade enabled the identification and advancement of a chemical series of 2-substituted phenol quinazolines with potent and selective RET inhibition.
- Profiling of clinical compounds confirmed the lack of RET-selective profiles in existing multi-kinase inhibitors.
Conclusions:
- The developed screening cascade is effective for identifying selective RET kinase inhibitors.
- The 2-substituted phenol quinazolines represent a promising chemical series for targeted RET inhibition.
- This work paves the way for developing novel therapeutics with improved safety profiles for RET-driven cancers.
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