ArticleThe Journal of biological chemistry2019
Structural basis of resistance of mutant RET protein-tyrosine kinase to its inhibitors nintedanib and vandetanib.
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 56 citations in OpenAlex.
- Imidazole-Functionalized Thieno[3,2-c]Quinoline Hybrids in Aggressive Medullary Thyroid Cancer Cell Models: Biological Evaluation and in Silico Insights.Pharmaceuticals (Basel, Switzerland) · 2026Article
- The oncogenic CCDC6-RET fusion protein is a dual ATP- and ADP-dependent kinase.Nature communications · 2026Article
- Modeling the Effects of Single Nucleotide Polymorphisms (SNPs) on the Structure and Function of the HumanHuman mutation · 2026Article
- Molecular genetics, therapeutics and RET inhibitor resistance for medullary thyroid carcinoma and future perspectives.Cell communication and signaling : CCS · 2024Review
- Review
- Generating Potential RET-Specific Inhibitors Using a Novel LSTM Encoder-Decoder Model.International journal of molecular sciences · 2024Article
- Design and Synthesis of Novel Thieno[3,2-ACS omega · 2023Article
- Medullary Thyroid Cancer: Updates and Challenges.Endocrine reviews · 2023Article
- Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations.Nature cancer · 2023Article
- Article
- Small Molecule Inhibitors as Therapeutic Agents Targeting Oncogenic Fusion Proteins: Current Status and Clinical.Molecules (Basel, Switzerland) · 2023Review
- Targeting RET Solvent-Front Mutants with Alkynyl Nicotinamide-Based Inhibitors.Molecular cancer therapeutics · 2023Article
- Response to Pralsetinib in Multi-Drug-Resistant Breast Cancer With CCDC6-RET Mutation.The oncologist · 2023Article
- Progress and challenges in RET-targeted cancer therapy.Frontiers of medicine · 2023Review
- Structural and dynamic determinants for highly selective RET kinase inhibition reveal cryptic druggability.Journal of advanced research · 2023Article
- Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective.Signal transduction and targeted therapy · 2022Review
- Pralsetinib: chemical and therapeutic development with FDA authorization for the management of RET fusion-positive non-small-cell lung cancers.Archives of pharmacal research · 2022Review
- Targeted therapy of RET fusion-positive non-small cell lung cancer.Frontiers in oncology · 2022Review
- RET kinase inhibitors forTherapeutic advances in medical oncology · 2022Review
- How does nintedanib overcome cancer drug-resistant mutation of RET protein-tyrosine kinase: insights from molecular dynamics simulations.Journal of molecular modeling · 2021Article
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 4 countries.
Funding
Abstract
RET is a transmembrane growth factor receptor. Aberrantly activated RET is found in several types of human cancer and is a target for treating RET aberration-associated cancer. Multiple clinically relevant RET protein-tyrosine kinase inhibitors (TKIs) have been identified, but how TKIs bind to RET is unknown except for vandetanib. Nintedanib is a RET TKI that inhibits the vandetanib-resistant RET(G810A) mutant. Here, we determined the X-ray co-crystal structure of RET kinase domain-nintedanib complex to 1.87 Å resolution and a RET(G810A) kinase domain crystal structure to 1.99 Å resolution. We also identified a vandetanib-resistant RET(L881V) mutation previously found in familial medullary thyroid carcinoma. Drug-sensitivity profiling of RET(L881V) revealed that it remains sensitive to nintedanib. The RET-nintedanib co-crystal structure disclosed that Leu-730 in RET engages in hydrophobic interactions with the piperazine, anilino, and phenyl groups of nintedanib, providing a structural basis for explaining that the p.L730V mutation identified in nine independently isolated cell lines resistant to nintedanib. Comparisons of RET-nintedanib, RET(G810A), and RET-vandetanib crystal structures suggested that the solvent-front Ala-810 makes hydrophobic contacts with a methyl group and aniline in nintedanib and blocks water access to two oxygen atoms of vandetanib, resulting in an energetic penalty for burying polar groups. Of note, even though the p.L881V mutation did not affect sensitivity to nintedanib, RET(L881V) was resistant to nintedanib analogs lacking a phenyl group. These results provide structural insights into resistance of RET mutants against the TKIs nintedanib and vandetanib.
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