ly3009120 has been researched along with Melanoma* in 2 studies
2 other study(ies) available for ly3009120 and Melanoma
| Article | Year |
|---|---|
Brain Distribution and Active Efflux of Three panRAF Inhibitors: Considerations in the Treatment of Melanoma Brain Metastases.
Targeted inhibition of RAF and MEK by molecularly targeted agents has been employed as a strategy to block aberrant mitogen-activated protein kinase (MAPK) signaling in melanoma. While the use of BRAF and MEK inhibitors, either as a single agent or in combination, improved efficacy in BRAF-mutant melanoma, initial responses are often followed by relapse due to acquired resistance. Moreover, some BRAF inhibitors are associated with paradoxical activation of the MAPK pathway, causing the development of secondary malignancies. The use of panRAF inhibitors, i.e., those that target all isoforms of RAF, may overcome paradoxical activation and resistance. The purpose of this study was to perform a quantitative assessment and evaluation of the influence of efflux mechanisms at the blood-brain barrier (BBB), in particular, Abcb1/P-glycoprotein (P-gp) and Abcg2/breast cancer resistance protein (Bcrp), on the brain distribution of three panRAF inhibitors: CCT196969 [1-(3-( Topics: Animals; Brain; Brain Neoplasms; Cell Line, Tumor; Dogs; Dose-Response Relationship, Drug; Female; Heterocyclic Compounds, 3-Ring; Humans; Madin Darby Canine Kidney Cells; Male; Melanoma; Mice; Mice, Knockout; Phenylurea Compounds; Phosphatidylethanolamine Binding Protein; Pyrazines; Pyrimidines | 2019 |
Development of Highly Sensitive Biosensors of RAF Dimerization in Cells.
The BRAF inhibitors dabrafenib and vemurafenib induce remarkable clinical responses in patients with BRAF-mutated melanomas. However, adverse events, including the emergence of secondary tumors and drug resistance, have been reported. Studies have revealed that undesirable RAF dimerization induced by inhibitors promotes these adverse effects. Here, we developed highly sensitive biosensors of RAF dimerization in cells utilizing the split enhanced click beetle luciferase (Emerald Luc, ELuc) complementation technique. We demonstrated that our biosensor system works effectively for high-throughput screens in the microplate format. A comprehensive analysis of commercially available RAF inhibitors performed using this assay system revealed that the inhibitors exhibit various potencies in inducing the dimerization of RAF isoforms, and their dimerization potencies do not always correlate with the RAF enzyme inhibition. This sensitive assay system will become a powerful tool to discover next-generation BRAF inhibitors with safer profiles. Topics: Benzothiazoles; Biosensing Techniques; Cell Line, Tumor; Dimerization; Heterocyclic Compounds, 2-Ring; Humans; Imidazoles; Melanoma; Nitriles; Oximes; Phenylurea Compounds; Protein Kinase Inhibitors; Protein Multimerization; Proto-Oncogene Proteins B-raf; Pyrimidines; Sulfonamides; Vemurafenib | 2019 |