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XL281

XL281 is a RAF kinase inhibitor under development by Exelixis Inc.

The NCI Drug Dictionary describes XL218 as follows: XL281 is an oral, selective small molecule inhibitor of wild-type and mutant RAF kinases, which lie downstream of RAS and are key components of the RAS/RAF/MEK/ERK kinase signaling pathway.  This pathway plays a key role in the transmission of growth-promoting signals downstream of receptor tyrosine kinases.  It is possible that deregulation of this pathway plays a pivotal role in the progression of many human tumors.

Specific to GIST, a small percent of patients with no mutations in the KIT gene (wildtype GIST) do show mutations in BRAF.  In addition some patients with mutant KIT show BRAF mutations after developing resistance to imatinib. For more about this, see the following paper:

Agaram NP, Wong GC, Guo T, Maki RG, Singer S, Dematteo RP, Besmer P, Antonescu CR.
 Novel V600E BRAF mutations in imatinib-naive and imatinib-resistantgastrointestinal stromal tumors.
Genes Chromosomes Cancer. 2008 Oct;47(10):853-9.
PMID: 18615679

Genetic lesions that activate this pathway are common in human tumors, with activating mutations in KRAS occurring in 30 percent of tumors and activating mutations in BRAF occurring in approximately 60 percent of melanomas.  XL281 potently inhibits BRAF, mutationally activated BRAF, and CRAF in vitro, and does not interact with kinases outside of the RAF family.  Pharmacodynamic analyses revealed substantial modulation of the BRAF signaling pathway in tumor tissue, skin, and hair, as indicated by decreases in the phosphorylation of MEK and ERK following treatment with XL281. A reduction in proliferation and an increase in apoptosis were observed in tumor tissue following treatment with XL281.

The developer of XL281, Exelixis, Inc., published the following comments in a press release following the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics held October, 2008 in Geneva, Switzerland:

“XL281 demonstrates clear target inhibition and exhibits early signs of clinical activity at generally well-tolerated doses in this phase 1 population," said Michael M. Morrissey, PhD, President of Research and Development at Exelixis. ..... "RAF is a very important target that is mutationally activated in numerous tumor types, and consequently there have been many attempts to directly inhibit this target. Based on our recent data, XL281 holds the potential to be an effective anti-cancer agent in a wide variety of tumor types."

"The on-target activity of XL281, coupled with its early signs of clinical activity, is highly encouraging and suggests that this agent may be effective in a wide range of tumor types," said Gary K. Schwartz, MD, Chief, Melanoma and Sarcoma Service, Memorial Sloan-Kettering Cancer Center.

Information on Exelixis and the press release for XL281

Preliminary clinicial data for XL281 Phase I trial for solid tumors at the Exelixis website

XL281 is currently in a Phase I trial described at clinicaltrials.gov NCT00451880 




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