Sorafenib C??? ??, ??, ??
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Sorafenib is a small molecular inhibitor of several kinases involved in tumor
angiogenesis and proliferation, including, but not limited to, Raf (IC
50=12nM for
Raf-1), VEGFR (IC
50=90nM for VEGFR-2 and IC
50=12nM for VEGFR-3),
and platelet derived growth factor receptor (IC
50=57nM for PDGFR-b). Specifically,
sorafenib blocks tumor progression by inhibiting cellular proliferation that is
dependent on activation of the MAPK pathway (Raf) and/or inhibiting tumor
angiogenesis through VEGFR and/or PDGFR. While it may be effective in the
treatment of a variety of tumors, the first approvable indication is for renal cell
carcinoma. Overall, the drug appears to be well tolerated by the majority
of patients at the 400 mg b.i.d. continuous dosing. As an inhibitor of multiple
kinases vital for tumor progression, sorafenib may possess wide-spectrum antitumor
properties and may emerge as an effective weapon against a variety of solid
tumors.
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Light Yellow Solid
Characteristics
Class: receptor tyrosine kinase
Treatment: RCC, HCC, thyroid cancer
Elimination half-life = 25–48 h
Protein binding = 99.7%
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Sorafenib Tosylate (Bay 43-9006, Nexavar) is a small molecular inhibitor of VEGFR, PDGFR, c-Raf and B-Raf with IC50s of 18 nM, 10 nM, 3 nM and 15 nM, respectively.
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ChEBI: Sorafenib is a member of the class of phenylureas that is urea in which one of the nitrogens is substituted by a 4-chloro-3-trifluorophenyl group while the other is substituted by a phenyl group which, in turn, is substituted at the para position by a [2-(methylcarbamoyl)pyridin-4-yl]oxy group. It has a role as an antineoplastic agent, an EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor, a tyrosine kinase inhibitor, an angiogenesis inhibitor, an anticoronaviral agent and a ferroptosis inducer. It is a pyridinecarboxamide, a member of monochlorobenzenes, an aromatic ether, a member of (trifluoromethyl)benzenes and a member of phenylureas.
Indications
Sorafenib (Nexavar(R), Bayer) was the first approved inhibitor targeting the vascular endothelial growth factor (VEGF) family kinases, which include VEGFR1, VEGR2, and VEGFR3. Sorafenib was originally approved for the treatment of renal cell carcinoma (RCC) in 2005, hepatocellular carcinoma in 2007, and locally recurrent or metastatic thyroid carcinoma refractory to radioactive iodine treatment in 2013. Six other approved inhibitors with VEGFRs as the main targets are sunitinib (Sutent(R), Pfizer) for RCC, soft tissue sarcoma, thyroid cancer,metastatic pancreatic tumors, gastrointestinal stromal tumor, and several other types of carcinomas; pazopanib (Votrient(R), GlaxoSmithKline) for RCC, soft tissue sarcoma, and thyroid cancer; axitinib (Inlyta(R), Pfizer) for RCC,thyroid cancer, and aplastic anemia, as well as T315I-mutant Bcr–Abl1-driven leukemia; regorafenib (Stivarga(R), Bayer) for gastrointestinal stromal tumors and colorectal cancer; nintedanib (Ofev(R), Boehringer Ingelheim) for the non-oncological indication of idiopathic pulmonary fibrosis; and lenvatinib (Lenvima(R), Eisai Inc.) for RCC and different types of thyroid cancers. Sunitinib, pazopanib, and lenvatinib bind to the “DFG-in”conformation of VEGFRs, while axitinib, regorafenib, and nintedanib bind to inactive VEGFRs adopting the “DFG-out”conformation.
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