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Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase.
- Source :
-
PloS one [PLoS One] 2015 Jun 05; Vol. 10 (6), pp. e0128364. Date of Electronic Publication: 2015 Jun 05 (Print Publication: 2015). - Publication Year :
- 2015
-
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.
- Subjects :
- Animals
Benzamides metabolism
Benzamides toxicity
Cell Line, Tumor
Cell Proliferation drug effects
Humans
Mice
Molecular Docking Simulation
Mutation
NIH 3T3 Cells
Niacinamide chemistry
Niacinamide metabolism
Niacinamide toxicity
Phosphorylation drug effects
Protein Binding
Protein Kinase Inhibitors metabolism
Protein Kinase Inhibitors toxicity
Protein Structure, Tertiary
Proto-Oncogene Proteins c-ret genetics
Proto-Oncogene Proteins c-ret metabolism
Pyridines metabolism
Pyridines toxicity
Small Molecule Libraries metabolism
Small Molecule Libraries toxicity
Transfection
Benzamides chemistry
Niacinamide analogs & derivatives
Protein Kinase Inhibitors chemistry
Proto-Oncogene Proteins c-ret antagonists & inhibitors
Pyridines chemistry
Small Molecule Libraries chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 10
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 26046350
- Full Text :
- https://doi.org/10.1371/journal.pone.0128364