Table 1.

BAY 43-9006 inhibits the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor angiogenesis

IC50 (nmol/L) ± SD (n)*
Biochemical assay
    Raf-16 ± 3 (7)
    BRAF wild-type§22 ± 6 (7)
    V599E BRAF mutant38 ± 9 (4)
    VEGFR-290 ± 15 (4)
    mVEGFR-2 (flk-ss1)15 ± 6 (4)
    mVEGR-320 ± 6 (3)
    mPDGFR-β57 ± 20 (5)
    Flt-358 ± 20 (3)
    c-KIT68 ± 21 (3)
    FGFR-1580 ± 100 (3)
    ERK-1, MEK-1, EGFR, HER-2, IGFR-1, c-met, PKB, PKA, cdk1/cyclinB, PKC, PKC, pim-11 > 10,000
    Cellular mechanism
    MDA MB 231 MEK phosphorylation (human breast)40 ± 20 (2)
    MDA MB 231 ERK 1/2 phosphorylation (human breast)90 ± 26 (7)
    BxPC-3 ERK 1/2 phosphorylation (human pancreatic)1,200** ± 165 (2)
    LOX ERK 1/2 phosphorylation (human melanoma)880** ± 90 (2)
    VEGFR-2 phosphorylation (human, NIH 3T3 cells)30 ± 21 (3)
    VEGF-ERK 1/2 phosphorylation (human, HUVEC)60** ± 26 (2)
    PDGFR-β phosphorylation (human HAoSMC)80 ± 40 (3)
    mVEGFR-3 phosphorylation (mouse, HEK-293 cells)100 ± 80 (2)
    Flt-3 phosphorylation (human ITD, HEK-293 cells)20 ± 10 (2)
    Cellular proliferation
    MDA MB 231 (10% FCS)2,600 ± 810 (3)
    PDGF-BB HAoSMC (0. 1% bovine serum albumin)280 ± 140 (5)
  • NOTE: Reproduced with permission from Wilhelm et al. (32).

  • * IC50 mean ± SD (n = number of trials).

  • Kinase assays were carried out at ATP concentrations at or below Km (1–10 μmol/L).

  • Lck activated NH2-terminal-truncated Raf-1.

  • § NH2-terminal-truncated BRAF (wild-type).

  • NH2-terminal V599E-truncated BRAF (mutant).

  • Cellular mechanism assays (receptor tyrosine kinase autophosphorylation and RAF/MEK/ERK pathway) were done in 0. 1% bovine serum albumin using phosphospecific antibodies or 4G10 for VEGFR-3.

  • ** Activated phospho-ERK 1/2 was quantitated with phospho-ERK 1/2 immunoassay (Bio-Plex; Bio-Rad, Hercules, CA).