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 approximately 5 years after the initiation of the first Phase I trial.

1 Pulmonary inflammatory diseases such as asthma are characterized by chronic, cell-mediated inflammation of the bronchial mucosa. 2 Recruitment and activation of inflammatory cells is orchestrated by a variety of mediators such as cytokines, chemokines, or adhesion molecules, the expression of which is regulated via the transcription factor nuclear factor kappa B (NF-kB). 3 NF-kB signaling is controlled by the inhibitor of kappa B kinase complex (IKK), a critical catalytic subunit of which is IKK-b. 4 We identified COMPOUND A as a small-molecule, ATP-competitive inhibitor selectively targeting IKK-b kinase activity with a K i value of 2 nM. 5 COMPOUND A inhibited stress-induced NF-kB transactivation, chemokine-, cytokine-, and adhesion molecule expression, and T-and B-cell proliferation. 6 COMPOUND A is orally bioavailable and inhibited the release of LPS-induced TNF-a in rodents. 7 In mice COMPOUND A inhibited cockroach allergen-induced airway inflammation and hyperreactivity and efficiently abrogated leukocyte trafficking induced by carrageenan in mice or by ovalbumin in a rat model of airway inflammation. 8 COMPOUND A was well tolerated by rodents over 3 weeks without affecting weight gain. 9 Furthermore, in mice COMPOUND A suppressed edema formation in response to arachidonic acid, phorbol ester, or edema induced by delayed-type hypersensitivity. 10 These data suggest that IKK-b inhibitors offer an effective therapeutic approach for inhibiting chronic pulmonary inflammation.

Raf kinase, an enzyme which acts downstream in the Ras signaling pathway, is involved in cancerous cell proliferation. Thus, small molecule inhibitors of Raf kinase activity may be important agents for the treatment of cancer. A novel class of Raf-1 inhibitors was discovered, using a combination of medicinal and combinatorial chemistry approaches. This effort culminated in the identification of the clinical candidate BAY 43-9006, currently undergoing Phase I clinical trials. The present review summarizes the medicinal chemistry development of ureas as highly potent inhibitors of Raf-1 kinase.

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