Background:

IC50: 0.13 nM against purified B-Raf V600E enzyme; a cellular pERK IC50 of 63 nM in the MALME-3M cell line

GDC-0879 is synthsized as a potent and selective B-Raf inhibitor. The Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase signaling pathway is reported to be involved in cellular responses, which is relevant to tumorigenesis.

In vitro: GDC-0879 is a B-Raf inhibitor against various in vitro and cell-based assays, such as A375 melanoma and Colo205 colorectal carcinoma cell lines, both of which are V600E B-Raf mutant. When screened against a panel of 140 kinases at its efficaciou dose, GDC-0879 showed expected activity only against C-Raf [1].

In vivo: In mice treated by GDC-0879, both cell line-and patient-derived BRAFV600E tumors exhibited stronger and more sustained pharmacodynamic inhibition (>90% for 8 hours) and improved survival compared with mutant KRAS-expressing tumors. Moreover, it was found that the responsiveness of BRAFV600E melanoma cells to GDC-0879 could be dramatically altered by pharmacologic and genetic modulation of phosphatidylinositol 3-kinase pathway activity [2].

Clinical trial: GDC-0879 is still in the preclinical development stage, and no clinical data are available currently.

参考文献:
[1] Wong H, Belvin M, Herter S, Hoeflich KP, Murray LJ, Wong L, Choo EF.? Pharmacodynamics of 2-[4-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridine-4-yl)-1H-pyrazol-1-yl]ethan-1-ol (GDC-0879), a potent and selective B-Raf kinase inhibitor: understanding relationships between systemic concentrations, phosphorylated mitogen-activated protein kinase kinase 1 inhibition, and efficacy. J Pharmacol Exp Ther. 2009 Apr;329(1):360-7.
[2] Hoeflich KP, Herter S, Tien J, Wong L, Berry L, Chan J, O'Brien C, Modrusan Z, Seshagiri S, Lackner M, Stern H, Choo E, Murray L, Friedman LS, Belvin M.? Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression. Cancer Res. 2009 Apr 1;69(7):3042-51.