GDC-0879

Female nu/nu mice

GDC-0879 is a novel potent, selective B-Raf inhibitor for B-RafV600E with IC50 of 0.13 nM.

0.5% methylcellulose/0.2% Tween 80

GDC-0879 also inhibits cellular pERK with IC50 of 63 nM. GDC-0879 shows comparable potency in A375 melanoma and Colo205 colorectal carcinoma cell lines, both of which are B-RafV600E mutant, with IC50 of 59 nM and 29 nM for pMEK1 inhibition respectively. GDC-0879 potently inhibits B-RafV600E in Malme3M cells with IC50 of 0.75 uM. GDC-0879 also shows EC50 values < 0.5 uM in many tumor cells (A375, 624, SK-MEL-28, Malme3M, C32, 928, 888, G-361, Colo205, Colo206, SW1417, CL34, and Colo201). [1]

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Data from [Proc Natl Acad Sci USA , 2011, 108, 6067-6072], GDC-0879purchased from Selleck, RAF inhibitors induce dimer formation between KSR and RAF, and activate KSR by CRAF. (A) GDC0879 but not PLX4720 induces BRAF/CRAF dimers. Cells overexpressing myc-CRAF and BRAF were treated with drug for 1 h and CRAF immunoprecipitates were immunoblotted for BRAF and CRAF (epitope tagged with myc). (B) GDC0879 but not PLX4720 enhances KSR/BRAF complexes. KSR immunoprecipitates were prepared from cells overexpressing FLAG-KSR and BRAF after treatment with the indicated drug for 1 h and immunoblotted using antibodies to BRAF. (C) Both GDC0879 and PLX4720 induce KSR/CRAF complexes.KSR immunoprecipitates were prepared from cells overexpressing FLAG-KSR and myc-CRAF after treatment with the indicated drug for 1 h and immunoblotted for CRAF using myc antibodies. (D and E) Requirement of KSR for drug-induced ERK activation. Lysates fromwild-type and KSR deficient fibroblasts, transfected with RASV12, were treated with the indicated doses of either GDC-0879 (D) or PLX4720 (E) for 1 h. Lysates were immunoblotted for phospho-ERK1 and 2, ERK2, and RASV12. (F) KSR and CRAF cooperate to activate MEK. Cells expressing the indicated constructs were treated with a 50 M PLX4720 for 2 h before cell lysates were prepared and analyzed for pMEK by immunoblotting. CRAF(TM) refers to the T421M gatekeeper mutant that cannot bind to the drug(4). (G) KSR in vitro kinase reactions. Cells were cotransfected with WT or ATP binding deficient KSR and CRAF and immunoprecipitates prepared after cells were treated with an activating dose of PLX (10 M) for 1 h. KSR immunoprecipitates were prepared, pretreated with 50 M PLX4720 to inhibit coprecipitating RAF activity, and then tested for kinase activity using purified MEK. MEK phosphorylation was detected using a pMEK specific antibody.

DMSO 67 mg/mL, Water <1 mg/mL, Ethanol 5 mg/mL