Sorafenib (Brand name: Nexavar, BAY 43-9006) is an oral anti-cancer drug approved by the U.S. Food and Drug Administration for the treatment of advanced renal cell carcinoma (December 2005) and unresectable hepatocellular carcinoma (November 2007). The small molecule multikinase inhibitor blocks tumor cell proliferation and angiogenesis by targeting various types of serine/threonine and receptor tyrosine kinases. Sorafenib is also in clinical trials for the treatment of thyroid, lung, and recurrent glioblastoma cancers. While the drug is generally well-tolerated, some adverse effects include skin rash, diarrhea, and hypertension. This pathway briefly reviews the pharmacodynamics of sorafenib.
Sorafenib inhibits tumor growth and progression by blocking multiple intracellular and cell surface kinases that are involved in regulating cancer phenotypes. In vitro biochemical assays demonstrate that sorafenib inhibits several members of the RAF/MEK/ERK signaling cascade, including serine/threonine kinases CRAF (IC50 = 6 nM), wild-type BRAF (IC50 = 25 nM), and V600E mutant BRAF (IC50 = 38nM) [Article:17016424]. In addition, sorafenib exerts its anti-cancer properties by inhibiting multiple pro-angiogenic receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR-1/2/3, IC50 = 26 nM, IC50 = 90 nM, and IC50 = 100 nM, respectively), platelet-derived growth factor receptor-B, (PDGFRB, IC50 = 80 nM), stem cell factor receptor (c-KIT, IC50 = 68 nM), fms-related tyrosine kinase 3 receptor (FLT3, IC50 = 33nM), fibroblast growth factor receptor 1 (FGFR1, IC50 = 580 nM), and RET tyrosine kinase (IC50 = 50 nM) [Articles:15466206, 16507829, 17016424]. The M2, M4, and M5 metabolites of sorafenib were also determined to potently inhibit VEGFR-2 (IC50 = 7 -10 nM), PDGFRB (IC50 =14 - 42 nM), and FLT3 (IC50 = 87 - 170 nM) in vitro.
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
If you would like to reproduce this PharmGKB pathway diagram:
Entities in the Pathway
Drugs/Drug Classes (1)
Relationships in the Pathway
|Arrow From||Arrow To||Controllers||PMID|
|AKT1||AKT1||PIK3C2A, PIK3C2B, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3|
|BRAF||BRAF||sorafenib, HRAS, KRAS, NRAS||15466206, 17016424|
|MAP2K1, MAP2K2||MAP2K1, MAP2K2||BRAF, RAF1|
|MAPK1, MAPK3||MAPK1, MAPK3||MAP2K1, MAP2K2|
|PIK3C2A, PIK3C2B, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3||PIK3C2A, PIK3C2B, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3R1, PIK3R2, PIK3R3||FLT1, FLT4, KDR|
|RAF1||RAF1||sorafenib, HRAS, KRAS, NRAS||15466206, 17016424|
|HRAS, KRAS, NRAS||HRAS, KRAS, NRAS||FGFR1, FLT1, FLT3, FLT4, KDR, KIT, PDGFRB, RET|
|FLT1, FLT4, KDR||FLT1, FLT4, KDR||sorafenib||15466206, 17016424|
Download data in TSV format. Other formats are available on the Downloads/LinkOuts tab.