Sorafenib kinase activation

Sorafenib (Nexavar) TKI Raf, VEGFR2, c-Kit, PDGFR, Flt-3, FGFR1 Inhibition of kinase activity - ATP-competitive RCC... 

Nexavar, A.49). Sorafenib inhibits VEGFR, PDGFR, and another protein kinase called Rafl kinase. Both sunitinib and sorafenib are active against some cancers of the kidney. Sunitinib is indicated against cancers of the gastrointestinal system as well, while sorafenib affects certain liver cancers. 

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. 

Several inhibitors of their tyrosine kinase activity (non-selective from one receptor to the other) are approved for cancer therapy (imatinib, erlotinib, sorafenib and smitinib) and many others are clinically studied (dasatinib, nilotinib, pazopanib, vatalanib, vandetanib...). 

Sorafenib is a kinase inhibitor with both antiproliferative and anti-angiogenic activity. Approved for the treatment of advanced renal cell carcinoma and for the treatment of patients with hepatocellular carcinoma. Peak plasma levels of sorafenib are generally observed 3 hours after oral administration. The... 

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). 

Fig. 1 Interaction network and domain structure of B-Raf. (a) Interaction network from the STRING database (http //string-db.org) for human proto-oncogene B-Raf. The lines indicate interactions between the proteins, with thickness of the lines reflecting confidence of the displayed interaction, (b) Domain structure of B-Raf and structures of individual domains, illustrating the different functional units that could be targeted by small molecule inhibitors B-Raf RBD in complex with Ras (PDB code 3kud), diacylglycerol binding Cl domain (lfaq) and the kinase domain in complex with active site inhibitor Sorafenib (luwh)...

As well as its effect on the translation of inhibitory potency against the intended target to cellular activity, the complex whole-cell situation can have a profound effect on the observed selectivity of kinase inhibitors. A small selection of data for the type II inhibitor sorafenib 8 demonstrates the potential for selectivity profiles to be different when comparing isolated enzyme or whole cell data, showing it to be a more potent inhibitor of Flt-3 relative to VEGFR-2, PDGFR-p and c-Kit in cells than would be predicted from its kinase inhibitory profile (Table 3.2).23 Probing the mechanistic basis for cellular kinase inhibitor selectivity, researchers at the University of California demonstrated that differential pathway sensitivity could lead to selective effects in cells.24... 

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