Bayer, sorafenib

Sorafenib is a reversible ATP-competitive inhibitor of multiple kinases developed by Bayer and Onyx. It was originally described as a C-Raf inhibitor, but has since been reported to inhibit B-Raf, p38a, KDR, and a several other... 

Fig. 14.6. Annotations for inhibitors that bind to unactivated kinase conformations. Sorafenib binds to the DGF-out conformation and its core is defined as Bayer like dfg. PD318088 binds to the aC-Glu-out conformation and its template is MEK like 3.

Sorafenib (l)11 is a multikinase inhibitor marketed by Bayer and Onyx. Sorafenib blocks tyrosine kinases as well as serine/threonine kinases. Its story began in 1994 when Bayer and Onyx entered a collaboration to discover novel Raf/MEK/ERK inhibitors. They first discovered a very mildly active compound 8 (/C50 17 pM) against Rafl kinase in 1995 from screening a collection of 200,000 compounds. The optimization of its potency and its ADMET profile using medicinal chemistry and combinatorial chemistry methods led to the identification of sorafenib (1) in 1999 as a preclinical development candidate. Multiple phase I studies started in 2000, when sorafenib tosylate (19) was evaluated in patents with advanced solid tumors of different types. In December 2005, Sorafenib tosylate (19) received U.S. FDA approval for the treatment of advanced renal cell carcinoma (RCC). Two years later, it was approved for the treatment of unresectable hepatocellular carcinoma (HCC). 

BAY 43-9006 (Sorafenib Bayer/Onyx Pharmaceuticals, Emeryville, CA) is a biaryl urea that inhibits Raf-1 kinase activity in vitro with IC50 value of 6nM, and B-Raf with IC50 value of 22 nM (25). This compound also inhibits some receptor tyrosine kinases, which include VEGF receptor family members, PDGF receptor. Fit, and c-Kit, at close to the same potency. 

Sorafenib / Nexavar d Bayer / Onyx Hepato/renal cell carcinoma Raf 464... 

Sorafenib Nexavar Bayer and Onyx 2005 VEGFR Renal cell carcinoma 126... 

PDGF receptor p (PDGFRB), and c-kit, a cytokine receptor expressed on the surface of hematopoietic stem cells as well as other cell types. As compared with the two drugs on the market, sorafenib (Nexavar) by Bayer Pharmaceuticals Corp. and Onyx Pharmaceuticals, Inc. and sunitinib (Sutent) by Pfizer, Inc., cediranib inhibits VEGFR targets with improved potency. It is currently in Phase II/III development for advanced non-small cell lung cancer and advanced colorectal cancer. 

Nexavar (Sorafenib tosylate). Bayer pic. UK Summary of product characteristics, January 2007. 

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