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Updated: Feb 28, 2026
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Discovery of wt RET and V804M RET Inhibitors: From Hit to Lead
Luca Mologni1, Martina Dalla Via2, Adriana Chilin2
1School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900, Monza, Italy.
Abstract:
Oncogenic activation of RET kinase has been found in several neoplastic diseases, like medullary thyroid carcinoma, multiple endocrine neoplasia, papillary thyroid carcinoma, and non-small-cell lung cancer. Currently approved RET inhibitors were not originally designed to be RET inhibitors, and their potency against RET kinase has not been optimized. Hence, novel compounds able to inhibit both wild-type RET (wt RET) and its mutants (e.g., V804M RET) are needed. Herein we present the development and the preliminary evaluation of a new sub-micromolar wt RET/V804M RET inhibitor, N-(2-fluoro-5-trifluoromethylphenyl)-N'-{4'-[(2''-benzamido)pyridin-4''-ylamino]phenyl}urea (69), endowed with a 4-anilinopyridine structure, starting from our previously identified 4-anilinopyrimidine hit compound. Profiling against a panel of kinases indicated 69 as a multi cKIT/wt RET/V804M RET inhibitor.
Insights
Researchers developed a novel compound, 69, that inhibits both wild-type RET (wt RET) and its V804M mutant. This new multi-kinase inhibitor shows promise for treating cancers driven by RET alterations.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Activating mutations in RET kinase are implicated in various cancers, including thyroid and lung cancers.
- Existing RET inhibitors lack optimized potency and specificity, necessitating the development of new therapeutic agents.
- Targeting both wild-type RET (wt RET) and its clinically relevant mutants, such as RET V804M, is crucial for effective cancer treatment.
Purpose of the Study:
- To design and synthesize novel compounds targeting both wt RET and RET V804M.
- To evaluate the inhibitory activity and selectivity of the developed compounds against RET kinase and other kinases.
Main Methods:
- Structure-based drug design utilizing a 4-anilinopyrimidine hit compound.
- Synthesis of a novel 4-anilinopyridine derivative, compound 69.
- In vitro kinase profiling of compound 69 against a panel of kinases, including wt RET and RET V804M.
Main Results:
- Compound 69, a novel 4-anilinopyridine derivative, was successfully synthesized.
- Compound 69 demonstrated sub-micromolar inhibitory activity against both wt RET and the RET V804M mutant.
- Kinase profiling revealed that compound 69 is a multi-target inhibitor, also affecting cKIT.
Conclusions:
- Compound 69 represents a promising novel inhibitor targeting wt RET and its V804M mutant.
- The multi-targeting profile of compound 69, including cKIT inhibition, warrants further investigation for potential therapeutic applications in RET-driven cancers.
