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Research Area
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Description
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Cancer |
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Biological Activity
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Description
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GDC-0879 is a novel potent, selective B-Raf inhibitor for B-RafV600E with IC50 of 0.13 nM. |
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Targets
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B-RafV600E |
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IC50 |
0.13 nM [1] |
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In Vitro
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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 an IC50 of 59 and 29 nM for pMEK1 inhibition respectively.[1] GDC-0879 potently inhibits BRAFV600E enzymatic activity in Malme3M cells with an IC50 of 0.75 μM.[1] All cells with GDC-0879 EC50 values <0.5 μm="" express="" v600e="" oncogenic="" alleles="" for="" braf="" (a375,="" 624,="" sk-mel-28,="" malme3m,="" c32,="" 928,="" 888,="" g-361,="" colo205,="" colo206,="" sw1417,="" cl34,="" and="" colo201).="">[1] |
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In Vivo
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In GDC-0879 treated mice, both cell line- and patient-derived BRAFV600E tumors exhibit stronger and more sustained pharmacodynamic inhibition (>90% for 8 hours) and improved survival compared to mutant KRAS-expressing tumors. Although there is involvement of activated RAF signaling in RAS-induced tumorigenesis, decreased time to progression is observed for some KRAS-mutant tumors following GDC-0879 administration. [2] Whereas GDC-0879-mediated efficacy is associated strictly with BRAFV600E status, MEK inhibition also attenuates 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. [2] |
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Clinical Trials
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Features
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Protocol
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Animal Study
[2]
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| Animal Models |
Female nu/nu mice |
| Formulation |
0.5% methylcellulose/0.2% Tween 80 |
| Doses |
100 mg/kg |
| Administration |
Oral gavage |
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