ArticleInvestigational new drugs2022
The return of RET GateKeeper mutations? an in-silico exploratory analysis of potential resistance mechanisms to novel RET macrocyclic inhibitor TPX-0046.
Article in Investigational new drugs, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
13 citing papers in PubMed, 1 synthesis or guideline pooled it, 16 citations in OpenAlex.
- Design of new drugs for medullary thyroid carcinoma.Frontiers in oncology · 2022Pooled it
- Modeling acquired TKI resistance and effective combination therapeutic strategies in murine RET+ lung adenocarcinoma.Cancer letters · 2026Article
- Combination of Selpercatinib and Trametinib Overcomes Resistance to RET Inhibitors in RET-Mutant Medullary Thyroid Carcinoma.JCO precision oncology · 2026Article
- Targeted therapy in thyroid cancer: molecular alterations and clinical management.Frontiers in endocrinology · 2026Review
- BYS10, a novel selective RET inhibitor, exhibits potent antitumor activity in preclinical models.Frontiers in pharmacology · 2025Article
- Review
- Targeting RET Solvent-Front Mutants with Alkynyl Nicotinamide-Based Inhibitors.Molecular cancer therapeutics · 2023Article
- The heterogeneous transition state of resistance to RET kinase inhibitors converges on ERK1/2-driven Aurora A/B kinases.Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy · 2023Article
- Progress and challenges in RET-targeted cancer therapy.Frontiers of medicine · 2023Review
- Treatment of Advanced Non-Small Cell Lung Cancer with RET Fusions: Reality and Hopes.International journal of molecular sciences · 2023Review
- A comprehensive overview of the relationship between RET gene and tumor occurrence.Frontiers in oncology · 2023Review
- Kinase Fusion-Related Thyroid Carcinomas: Towards Predictive Models for Advanced Actionable Diagnostics.Endocrine pathology · 2022Review
- Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
TPX-0046 is designed to overcome resistance to FDA approved RET inhibitors Selpercatinib and Pralsetinib. Early prediction of resistance mechanisms to investigational drugs may facilitate subsequent drug and trial designs. This study aims to predict potential mutations inducing resistance to TPX-0046. We conducted an in-silico analysis of TPX-0046 macrocyclic structure and predicted the binding mode on RET. We used as reference literary examples of resistance mechanisms to other macrocyclic inhibitors (Lorlatinib on ALK/ROS1) to construct RET secondary resistance mutations. We conducted docking simulations to evaluate impact of mutations on TPX-0046 binding. TPX-0046 binding mode on RET appears to not be influenced by Solventfront G810X mutation presence. Bulky Gatekeeper V804X mutations affect predicted TPX-0046 binding mode. Mutations in Beta 7 strand region L881F and xDFG S891L impair TPX-0046 docking. Our findings suggest that development of second generation RET inhibitors focused mainly on Solventfront G810X mutations granting resistance to selective RET inhibitors Selpercatinib and Pralsetinib. If these findings are confirmed by identification of Gatekeeper V804X mutations in patients progressing to TPX-0046, explanation of acquired resistance and loss of benefit will be easier These findings might accelerate development of third generation RET inhibitors, as well as clinical trial design in precision oncology settings.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.