Chemical Name : GDC-0879/GDC0879
CAS : 905281-76-7
Synonyms: (E)-2,3-Dihydro-5-[1-(2-hydroxyethy l)-3-(4-pyridinyl)-1H-pyrazol-4-yl]-1H-inden-1-one oxime
Storage:-20C 2 years
GDC-0879 is a highly selective, novel potent, orally bioavailable B-Raf inhibitor in various in vitro and cell-based assays with an IC50 estimate of 0.13 nM against purified B-Raf V600E enzyme and a cellular pERK IC50 of 63 nM in the MALME-3M cell line.For this compound, subnanomolar enzyme potency translated into very effective reduction of cellular viability of BRAF-mutant Malme3M cells (EC50 values were 0.75 umol/L for GDC-0879).In GDC-0879-treated mice, 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.
Whereas GDC-0879–mediated efficacy was associated strictly with BRAFV600E status, MEK inhibition also attenuated proliferation and tumor growth of cell lines expressing wild-type BRAF (81% KRAS mutant, 38% KRAS wild type). The responsiveness of BRAFV600E melanoma cells to GDC-0879 could be dramatically altered by pharmacologic and genetic modulation of phosphatidylinositol 3-kinase pathway activity. These data suggest that GDC-0879–induced signaling changes are dependent on the point of oncogenic activation within the RAS network
1. Choo EF, Driscoll JP, Feng J, Liederer B, Plise E, Randolph N, Shin Y, Wong S, Ran Y. Disposition of GDC-0879, a B-RAF kinase inhibitor in preclinical species. Xenobiotica. 2009 Sep;39(9):700-9.
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. Epub 2009 Mar 10.