title: XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC.
abstract: XL-184 (BMS-907351), under development by Exelixis Inc and Bristol-Myers Squibb Co, is a pan-tyrosine kinase inhibitor for the potential oral treatment of medullary thyroid cancer, glioblastoma multiforme and NSCLC. The prinicipal targets of XL-184 are MET, VEGFR-2 and RET, but the drug is also reported to display inhibitory activity against KIT, FLT3 and TEK. Preclinical studies demonstrated that XL-184 potently inhibited multiple receptor tyrosine kinases in various cancer cell lines and animal xenograft models, and that the drug exhibited significant oral bioavailability and blood-brain barrier penetration. A phase I clinical trial in patients with advanced solid malignancies indicated that XL-184 accumulated dose-dependently in the plasma and had a long terminal half-life. A phase II trial in patients with progressive or recurrent glioblastoma revealed modest but promising median progression-free survival. Toxicity and side effects for the drug have generally been of low-to-moderate severity. At the time of publication, three additional trials of XL-184 were recruiting patients, including a phase I trial in combination with standard of care in patients with glioblastoma, a phase I/II trial in combination with erlotinib in patients with NSCLC, and a phase III trial in patients with medullary thyroid cancer.
authors.affiliation: University of Virginia, Department of Microbiology, PO Box 800168, Charlottesville, Virginia, 22903, USA. ra6u@virginia.edu
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fadila
authors.initials: F
authors.lastname: Guessous
authors.forename: Alex
authors.initials: A
authors.lastname: Kofman
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.forename: Roger
authors.initials: R
authors.lastname: Abounader
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D018276:Carcinoma, Medullary / Q000188:drug therapy / Q000503:physiopathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000503:physiopathology; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D005909:Glioblastoma / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors