ArticlePloS one2015
Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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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, 20 citations in OpenAlex.
- Article
- An integrative pan cancer analysis of RET aberrations and their potential clinical implications.Scientific reports · 2022Article
- Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors.Molecules (Basel, Switzerland) · 2021Review
- Analysis of Cell-Free DNA from 32,989 Advanced Cancers Reveals Novel Co-occurring ActivatingClinical cancer research : an official journal of the American Association for Cancer Research · 2019Article
- Role of EphA2-PI3K signaling in vasculogenic mimicry induced by cancer-associated fibroblasts in gastric cancer cells.Oncology letters · 2019Article
- Inferring Novel Tumor Suppressor Genes with a Protein-Protein Interaction Network and Network Diffusion Algorithms.Molecular therapy. Methods & clinical development · 2018Article
- Cancer-associated fibroblasts promote gastric tumorigenesis through EphA2 activation in a ligand-independent manner.Journal of cancer research and clinical oncology · 2018Article
- Discovery of a First-in-Class Gut-Restricted RET Kinase Inhibitor as a Clinical Candidate for the Treatment of IBS.ACS medicinal chemistry letters · 2018Article
- Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes.Nature reviews. Clinical oncology · 2018Review
- A Novel EphA2 Inhibitor Exerts Beneficial Effects in PI-IBSFrontiers in pharmacology · 2018Article
- Article
- Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers.Oncogene · 2017Article
- The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer.Best practice & research. Clinical endocrinology & metabolism · 2017Review
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 4 countries.
Funding
Abstract
Oncogenic mutation of the RET receptor tyrosine kinase is observed in several human malignancies. Here, we describe three novel type II RET tyrosine kinase inhibitors (TKI), ALW-II-41-27, XMD15-44 and HG-6-63-01, that inhibit the cellular activity of oncogenic RET mutants at two digit nanomolar concentration. These three compounds shared a 3-trifluoromethyl-4-methylpiperazinephenyl pharmacophore that stabilizes the 'DFG-out' inactive conformation of RET activation loop. They blocked RET-mediated signaling and proliferation with an IC50 in the nM range in fibroblasts transformed by the RET/C634R and RET/M918T oncogenes. They also inhibited autophosphorylation of several additional oncogenic RET-derived point mutants and chimeric oncogenes. At a concentration of 10 nM, ALW-II-41-27, XMD15-44 and HG-6-63-01 inhibited RET kinase and signaling in human thyroid cancer cell lines carrying oncogenic RET alleles; they also inhibited proliferation of cancer, but not non-tumoral Nthy-ori-3-1, thyroid cells, with an IC50 in the nM range. The three compounds were capable of inhibiting the 'gatekeeper' V804M mutant which confers substantial resistance to established RET inhibitors. In conclusion, we have identified a type II TKI scaffold, shared by ALW-II-41-27, XMD15-44 and HG-6-63-01, that may be used as novel lead for the development of novel agents for the treatment of cancers harboring oncogenic activation of RET.
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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.