GDC-0879

N. catalogoS1104 Lotto:S110406

Stampa

Dati tecnici

Formula

C19H18N4O2
Peso molecolare 334.37 Numero CAS 905281-76-7
Solubilità (25°C)* In vitro Ethanol 5 mg/mL (14.95 mM)
DMSO 2 mg/mL (5.98 mM)
Water Insoluble
In vivo (Aggiungere i solventi al prodotto singolarmente e in ordine.)
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
* <1 mg/ml significa leggermente solubile o insolubile.
* Si prega di notare che Selleck testa la solubilità di tutti i composti internamente e la solubilità effettiva può differire leggermente dai valori pubblicati. Ciò è normale ed è dovuto a leggere variazioni da lotto a lotto.
* Spedizione a temperatura ambiente (I test di stabilità mostrano che questo prodotto può essere spedito senza alcuna misura di raffreddamento.)

Preparazione delle soluzioni stock

Attività biologica

Descrizione GDC-0879 (AR-00341677) è un inibitore di B-Raf nuovo, potente e selettivo con un IC50 di 0,13 nM nelle cellule A375 e Colo205 con attività anche contro c-Raf; nessuna inibizione nota di altre protein chinasi.
Target
B-Raf
(A375, Colo205 cells)
0.13 nM
In vitro GDC-0879 also inhibits cellular pERK with IC50 of 63 nM. This compound 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. It potently inhibits B-RafV600E in Malme3M cells with IC50 of 0.75 μM. This chemical also shows EC50 values < 0.5 μM in many tumor cells (A375, 624, SK-MEL-28, Malme3M, C32, 928, 888, G-361, Colo205, Colo206, SW1417, CL34, and Colo201).
In vivo 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 this compound administration. Whereas this chemical-mediated efficacy is associated strictly with B-RafV600E 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 B-RafV600E melanoma cells to this agent could be dramatically altered by pharmacologic and genetic modulation of PI3K pathway activity.

Protocollo (da riferimento)

Studio sugli animali:[2]
  • Modelli animali

    Female nu/nu mice

  • Dosaggi

    100 mg/kg

  • Somministrazione

    Oral gavage

Riferimenti

  • https://pubmed.ncbi.nlm.nih.gov/19147858/
  • https://pubmed.ncbi.nlm.nih.gov/19276360/

Convalida del prodotto da parte del cliente

<p> </p><p>Melanoma cell viability and in vivo growth by cyclindependent kinase 2/4 inhibition. Western blot analysis for c-Jun, phosphorylated-ERK1/2 (Thr202/Tyr204) (p-ERK1/2), and total ERK1/2 protein levels was done for human melanoma cell lines treated with the BRAFV600E inhibitor GDC-0879 (1 μM), or MEK inhibitors CI-1040 (1 μM), U0126 (1 μM), and PD98059 (10 μM) for 18 hours.</p>

Dati da [ J Natl Cancer Inst , 2012 , 104(21), 1673-9 ]

<p>Melanoma cell viability and in vivo growth by cyclindependent kinase 2/4 inhibition. In vivo growth of LOXIMVI xenografts in athymic nude Foxn1nu mice is shown. Tumors were allowed to grow to a maximum volume of 250mm<sup>3</sup>, and the mice were subsequently treated daily at the indicated dose levels with CDK2/4 inhibitors by intraperitoneal injection in combination with a BRAFV600E- or MEK-inhibitor. CDK2/4 inhibitor (CVT-313/indolocarbazole CDK4-I) treatment sensitizes tumors to GDC-0879 and CI1040.</p>

Dati da [ J Natl Cancer Inst , 2012 , 104(21), 1673-9 ]

<p>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 μM 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 μM) for 1 h. KSR immunoprecipitates were prepared, pretreated with 50 μM PLX4720 to inhibit coprecipitating RAF activity, and then tested for kinase activity using purified MEK. MEK phosphorylation was detected using a pMEK specific antibody.</p>

Dati da [ Proc Natl Acad Sci USA , 2011 , 108, 6067-6072 ]

<p>B-RafV600E mutated melanoma line, A375, was treated with different doses of GDC0879 for 1 h or 24 h. Cell lysates were analyzed by Western blotting to determine the levels of phosphorylated MEK1/2 (pMEK1/2) and phosphorylated ERK1/2 (pERK1/2).</p><div><div> </div></div><p> </p>

, , Dr. Jong-in Park from Medical College of Wisconsin

Selleck's GDC-0879 È stato citato da 49 Pubblicazioni

A structure-based modelling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia [ bioRxiv, May 03, 2025, nan] PubMed: 40654850
Bioluminescence-based assays for quantifying endogenous protein interactions in live cells [ J Biol Chem, 2025, 301(8):110454] PubMed: 40617353
BH4 Oxidation-Derived H2O2 Activates ERK1/2 Signaling via B-Raf in Rat Dorsal Root Ganglion Neurons [ J Neurochem, 2025, 169(11):e70271] PubMed: 41178527
A structure-based modelling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia [ bioRxiv, 2025, 2025.04.29.651188] PubMed: 40654850
Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer [ Nature, 2024, 629(8013):927-936] PubMed: 38588697
Analysis of RAS and drug induced homo- and heterodimerization of RAF and KSR1 proteins in living cells using split Nanoluc luciferase [ Cell Communication and Signaling, 2023 Jun 14, 136] PubMed: 37316874
BRAFΔβ3-αC in-frame deletion mutants differ in their dimerization propensity, HSP90 dependence, and druggability [ Sci Adv, 2023, 9(35):eade7486] PubMed: 37656784
Integrative analysis of drug response and clinical outcome in acute myeloid leukemia [ Cancer Cell, 2022, S1535-6108(22)00312-9] PubMed: 35868306
Inhibition of IκB Kinase Is a Potential Therapeutic Strategy to Circumvent Resistance to Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer Cells [ Cancers (Basel), 2022, 14(21)5215] PubMed: 36358633
AKT1/FOXP3 axis-mediated expression of CerS6 promotes p53 mutant pancreatic tumorigenesis [ Cancer Lett, 2021, S0304-3835(21)00309-8] PubMed: 34343636

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