GDC-0879 - CAS 905281-76-7
Catalog number: 905281-76-7
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
GDC-0879, a highly selective, potent, and orally bioavailable RAF small-molecule inhibitor. In GDC-0879-treated mice, both cell line- and patient-derived BRAF(V600E) tumors exhibited stronger and more sustained pharmacodynamic inhibition (>90% for 8 hours) and improved survival compared with mutant KRAS-expressing tumors. Despite the involvement of activated RAF signaling in RAS-induced tumorigenesis, decreased time to progression was observed for some KRAS-mutant tumors following GDC-0879 administration. Moreover, striking differences were noted for RAF and MEK inhibition across a panel of 130 tumor cell lines. Whereas GDC-0879-mediated efficacy was associated strictly with BRAF(V600E) 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 BRAF(V600E) 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. Taken together, these studies increase our understanding of the molecular determinants for antitumor efficacy resulting from RAF pathway inhibition and have implications for therapeutic intervention in the clinic.
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1.Skin tumorigenesis stimulated by Raf inhibitors relies upon Raf functions that are dependent and independent of ERK.
Doma E1, Rupp C, Varga A, Kern F, Riegler B, Baccarini M. Cancer Res. 2013 Dec 1;73(23):6926-37. doi: 10.1158/0008-5472.CAN-13-0748. Epub 2013 Oct 15.
RAF inhibitors achieve unprecedented but mainly transient clinical responses in patients with melanoma whose tumors harbor an activating BRAF mutation. One notable side-effect of RAF inhibitors is the stimulation of cutaneous skin tumors, arising in about 30% of patients receiving these drugs, which are thought to develop as a result of inhibitor-induced activation of wild-type Raf in occult precursor skin lesions. This effect raises the possibility that less manageable tumors might also arise in other epithelial tissues. Here we provide preclinical evidence supporting this disquieting hypothesis by showing that the RAF inhibitors PLX-4032 (vemurafenib) and GDC-0879 precipitate the development of cell-autonomous, Ras-driven tumors in skin and gastric epithelia. The magnitude of the effects correlated with the inhibitors' relative abilities to induce ERK activation. Epidermis-restricted ablation of either B-Raf or C-Raf prevented PLX-4032-induced ERK activation and tumorigenesis.
2.Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF.
Hu J1, Yu H, Kornev AP, Zhao J, Filbert EL, Taylor SS, Shaw AS. Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6067-72. doi: 10.1073/pnas.1102554108. Epub 2011 Mar 25.
Because mutations in RAS and BRAF represent the most common mutations found in human tumors, identification of inhibitors has been a major goal. Surprisingly, new oncogenic BRAF specific inhibitors inhibit cells transformed with mutated BRAF but paradoxically stimulate the growth of cells transformed with RAS. Here, we show that the mechanism for activation is via drug-induced dimer formation between CRAF and kinase suppressor of Ras (KSR)1. To understand the function of KSR1, we generated a KSR1 mutant that cannot bind ATP but stabilizes the closed, active conformation of KSR1. Molecular modeling suggested that the mutant stabilizes the two hydrophobic spines critical for the closed active conformation. We, therefore, could use the mutant to discriminate between the scaffold versus kinase functions of KSR1. The KSR1 mutant bound constitutively to RAF and mitogen-activated protein kinase kinase (MEK) but could not reconstitute activity suggesting that the catalytic activity of KSR1 is required for its function.
3.Disposition of GDC-0879, a B-RAF kinase inhibitor in preclinical species.
Choo EF1, Driscoll JP, Feng J, Liederer B, Plise E, Randolph N, Shin Y, Wong S, Ran Y. Xenobiotica. 2009 Sep;39(9):700-9. doi: 10.1080/00498250902991827.
1. The pharmacokinetics and disposition of GDC-0879, a small molecule B-RAF kinase inhibitor, was characterized in mouse, rat, dog, and monkey. 2. In mouse and monkey, clearance (CL) of GDC-0879 was moderate (18.7-24.3 and 14.5 +/- 2.1 ml min(-1) kg(-1), respectively), low in dog (5.84 +/- 1.06 ml min(-1) kg(-1)) and high in rat (86.9 +/- 14.2 ml min(-1) kg(-1)). The volume of distribution across species ranged from 0.49 to 1.9 l kg(-1). Mean terminal half-life values ranged from 0.28 h in rats to 2.97 h in dogs. Absolute oral bioavailability ranged from 18% in dog to 65% in mouse. 3. Plasma protein binding of GDC-0879 in mouse, rat, dog, monkey, and humans ranged from 68.8% to 81.9%. 4. In dog, the major ketone metabolite (G-030748) of GDC-0879 appeared to be formation rate-limited. 5. Based on assessment in dogs, the absorption of GDC-0879 appeared to be sensitive to changes in gut pH, food and salt form (solubililty), with approximately three- to four-fold change in areas under the curve (AUCs) observed.
4.Validation and application of a liquid chromatography-tandem mass spectrometric method for the determination of GDC-0879 and its metabolite in dog plasma using solid phase extraction.
Chou B1, Adler RS, Meng M, Percey S, Dean B, Hop CE, Shin YG. J Pharm Biomed Anal. 2012 Nov;70:354-61. doi: 10.1016/j.jpba.2012.05.029. Epub 2012 Jun 1.
A liquid-chromatographic-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of GDC-0879 and its ketone metabolite (M1) in dog plasma to support preclinical toxicokinetic evaluation. The method consisted of solid phase extraction for sample preparation and LC-MS/MS analysis in positive ion mode using electrospray ionization for analysis. D(4)-GDC-0879 and (13)C(2)-D(2)-M1 were used as internal standards. A quadratic regression (weighted 1/concentration(2)) was used to fit calibration curves over the concentration range of 1-1000 ng/ml for both GDC-0879 and M1. The accuracy (%bias) at the lower limit of quantitation (LLOQ) was 12.0% and 2.0% for GDC-0879 and M1, respectively. The precision (%CV) for samples at the LLOQ was 11.3% and 2.6% for GDC-0879 and M1, respectively. For quality control samples at 3.00, 400 and 800 ng/ml, the between run %CV was ≤3.9% for GDC-0879 and ≤2.4% for M1. Between run %bias ranged from 4.
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