Discovery and development of sorafenib: a multikinase inhibitor for treating cancer

By S. Wilhelm, Christopher A. Carter, M. Lynch, T. Lowinger, J. Dumas, Roger A. Smith, B. Schwartz, R. Simantov, S. Kelley. Nature reviews. Drug discovery, 2006

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Since the molecular revolution of the 1980s, knowledge of the aetiology of cancer has increased considerably, which has led to the discovery and development of targeted therapies tailored to inhibit cancer-specific pathways. The introduction and refinement of rapid, high-throughput screening technologies over the past decade has greatly facilitated this targeted discovery and development process. Here, we describe the discovery and continuing development of sorafenib (previously known as BAY 43-9006), the first oral multikinase inhibitor that targets Raf and affects tumour signalling and the tumour vasculature. The discovery cycle of sorafenib (Nexavar; Bayer Pharmaceuticals) — from initial screening for a lead compound to FDA approval for the treatment of advanced renal cell carcinoma in December 2005 — was completed in just 11 years, with approval being received ∼5 years after the initiation of the first Phase I trial.

Subfields: Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/123758650b561e15f9df4ac533aaa085c806aab1

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Citations in the corpus

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma (2010, background): “In addition, sorafenib inhibits vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), c-kit, Flt-3, and RET (IC50 \ 100 nM) [347].”
Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: Subanalyses of a phase III trial , (2012, background): “Sorafenib is a multitargeted tyrosine kinase inhibitor that blocks the activity of Raf serine/threonine kinase isoforms, as well as the receptor tyrosine kinases vascular endothelial growth factor receptors (VEGFR)-2 and -3, platelet-derived growth factor receptor (PDGFR) b, c-KIT, FLT-3, and RET, t”
Current Strategy for Staging and Treatment: The BCLC Update and Future Prospects (2010, methodology): “This agent is an oral tyrosine kinase inhibitor that blocks the Raf/MEK/ ERK pathway and the receptor for VEGFR 2 and PDGFR-b.121,122 After showing activity in experimental models and potential delayed tumor progression rate in a large phase 2 study,123 it was tested in a phase III, multicenter, ran”
Ferroptosis, a new form of cell death, and its relationships with tumourous diseases (2016, background): “In addition, because sorafenib is also a ferroptosis inducer, its clinical effectiveness in RCC treatment [89] indirectly supports the existence of ferroptosis in RCC.”
Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis (2014, background): “The observation that sorafenib (BAY 43-9006, Nexavar), a multi-kinase inhibitor clinically approved for the treatment of renal cell carcinoma (Wilhelm et al., 2006), could synergize with erastin or BSO treatment was unexpected, and suggested that sorafenib could affect the ferroptosis pathway.”
Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update (2017, background): “Sorafenib, a multikinase inhibitor of Raf, vascular endothelial growth factor receptor (VEGFR), plateletderived growth factor receptor (PDGFR), c-kit, Flt-3, and RET [575], has been approved for the treatment of advanced HCC in patients with Child–Pugh class A liver function worldwide.”