sorafenib brands

Molecular formula: C21H16ClF3N4O3

Kinases are involved in tumour cell signalling, proliferation, angiogenesis, and apoptosis. Sorafenib inhibits multiple intracellular serine/threonine kinases in the Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway. Intracellular Raf serine/threonine kinase isoforms inhibited by sorafenib include Raf-1 (or C-Raf), wild-type B-Raf, and mutant B-Raf. Sorafenib inhibits cell surface tyrosine kinase receptors such as KIT, FMS-like tyrosine kinase 3 (FLT-3), RET, RET/PTC, vascular endothelial growth factor receptor-1 (VEGFR-1), VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor-β (PDGFR-β). Sorafenib is thought to exhibit a dual mechanism of action: it blocks tumour proliferation and growth by inhibiting the RAF/MEK/extracellular signal-regulated kinase (ERK) pathway on tumour cells, and reduces tumour angiogenesis by inhibiting VEGFR and PDGFR signalling in tumour vasculature. Sorafenib is U.S. Food and Drug Administration-approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers. Unfortunately, as with other RAF inhibitors, patients treated with sorafenib have a 5% to 10% rate of developing cutaneous squamous cell carcinoma (cSCC)/keratoacanthomas. Paradoxical activation of extracellular signal-regulated kinase (ERK) in BRAF wild-type cells has been implicated in RAF inhibitor-induced cSCC. Here, /the researchers/ report that sorafenib suppresses UV-induced apoptosis specifically by inhibiting c-jun-NH2-kinase (JNK) activation through the off-target inhibition of leucine zipper and sterile alpha motif-containing kinase (ZAK). Our results implicate suppression of JNK signaling, independent of the ERK pathway, as an additional mechanism of adverse effects of sorafenib. This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis. Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)(5/6/7) repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration. Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype. Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC(50) = 18 umol/L; K(i) = 11.7 umol/L) in vitro. Five patients carrying UGT1A1*28/*28 (n = 4) or UGT1A9*3/*3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n = 12 and n = 5; R(2) = 0.38 and R(2) = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure. This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and

Source: PubChem (NCBI) · compound 216239