BAY 43-9006 is the first oral Raf kinase inhibitor to undergo clinical testing. In cellular assays, BAY 43-9006 demonstrated inhibition of the MAPK pathway in colon, pancreatic, and breast tumor cell lines. In addition, BAY 43-9006 had significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including VEGFR-2, VEGFR-3, PDGFR-β, Flt-3, and c-KIT. The effects of BAY 43-9006 on Mcl-1, a potent anti-apoptotic protein of the Bcl-2 family, have been examined in multiple human malignant cell lines. Treatment of A549 NSCLC cells with BAY 43-9006 significantly reduces Mcl-1 levels in a time- and dose-dependent manner. Similarly, Mcl-1 down-regulation is seen in other cancer cell lines (ACHN, kidney; HT-29, colon; MDA-MB-231, breast; and K562, leukemia) with BAY 43-9006 treatment. There is, however, no change in Mcl-1 mRNA levels in cells exposed to BAY 43-9006, as measured by RT-PCR, indicating that the down-regulation of Mcl-1 is a result of a post-translational change. Mcl-1 over-expression markedly diminishes BAY 43-9006-induced apoptosis, a process which is accompanied by blockage of caspase cleavage and cytochrome c release to the cytosol, while Mcl-1 down-regulation sensitizes cells to BAY 43-9006-induced apoptosis. Finally, the pan-caspase inhibitor BOC-D-fmk completely blocks BAY 43-9006-induced apoptosis. BOC-D fmk failed to block cytochrome c release into the cytosolic S-100 fraction, but did abrogate caspase 3 and 8 cleavage, indicating that mitochondrial dysfunction is upstream of the caspase cascade. Collectively, these findings demonstrate that drug-induced Mcl-1 degradation contributes to the pro-apoptotic effects of BAY 43-9006.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]