Article

Selective Raf inhibition in cancer therapy

NexusPharma, Inc., Langhorne, PA 19047, USA.
Expert Opinion on Therapeutic Targets (Impact Factor: 5.14). 01/2008; 11(12):1587-609. DOI: 10.1517/14728222.11.12.1587
Source: PubMed

ABSTRACT

Over the past 5 years, the Raf kinase family has emerged as a promising target for protein-directed cancer therapy development. The goal of this review is to first provide a concise summary of the data validating Raf proteins as high-interest therapeutic targets. The authors then outline the mode of action of Raf kinases, emphasizing how Raf activities and protein interactions suggest specific approaches to inhibiting Raf. The authors then summarize the set of drugs, antisense reagents and antibodies available or in development for therapeutically targeting Raf or Raf-related proteins, as well as existing strategies combining these and other therapeutic agents. Finally, the authors discuss recent results from systems biology analyses that have the potential to increasingly guide the intelligent selection of combination therapies involving Raf-targeting agents and other therapeutics.

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Available from: Erica A Golemis
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    • ", [64] LErafAON c-Raf-1 (rafAON) [75] LErafAON [66] , LErafAON [76] , c-Raf-1 mRNA , , "
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    • "Newer Raf kinase inhibitors such as PLX4032 [15] and its later derivatives, intended to be selective for mutationally activated B-Raf (V600E), are also under development [16]. Extensive investment has also been made in MEK inhibitors including CI-1040, AZD6244 and others [6,8,9,17], although none has yet proven efficacious as single agent therapy. "
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    • "However, sorafenib is a multikinase inhibitor and its clinical antitumor activity is probably a result of its activity against proangiogenic receptor tyrosine kinases, such as vascular endothelial growth factor receptor and plateletderived growth factor receptor (Li et al., 2007). Other reported Raf inhibitors include PLX4032, ZM336372, AZ628, AAL881, LBT613, SB-590885, and RAF-265 (Khazak et al., 2007; Li et al., 2007). To date, little or no detailed analysis of the pharmacokinetic-pharmacodynamic (PK-PD) relationships between systemic exposure of a Raf inhibitor and its effects on downstream markers of pathway modulation have been published. "
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