2-{4-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridin-4-yl)-1H-pyrazol-1-yl}ethan-1-ol

• ChemBase ID: 72513
• Molecular Formular: C19H18N4O2
• Molecular Mass: 334.37182
• Monoisotopic Mass: 334.14297584
• SMILES: C(Cn1nc(c(c1)c1ccc2c(c1)CC/C/2=N\O)c1ccncc1)O
• Canonical SMILES: OCCn1cc(c(n1)c1ccncc1)c1ccc2c(c1)CC/C/2=N\O
• InChI: InChI=1S/C19H18N4O2/c24-10-9-23-12-17(19(21-23)13-5-7-20-8-6-13)15-1-3-16-14(11-15)2-4-18(16)22-25/h1,3,5-8,11-12,24-25H,2,4,9-10H2/b22-18+
• InChIKey: DEZZLWQELQORIU-RELWKKBWSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 2-{4-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridin-4-yl)-1H-pyrazol-1-yl}ethan-1-ol
• IUPAC Traditional name: 2-{4-[(1E)-1-(hydroxyimino)-2,3-dihydroinden-5-yl]-3-(pyridin-4-yl)pyrazol-1-yl}ethanol
• Synonyms: GDC-0879

Database IDs

• CAS Number: 905281-76-7
• PubChem SID: 162037438
• PubChem CID: 11717001

CALCULATED PROPERTIES

• Acid pKa: 8.37974
• H Acceptors: 5
• H Donor: 2
• LogD (pH = 5.5): 2.0387444
• LogD (pH = 7.4): 2.0032456
• Log P: 2.0464225
• Molar Refractivity: 106.4866 cm^3
• Polarizability: 38.510014 Å^3
• Polar Surface Area: 83.53 Å^2
• Rotatable Bonds: 4
• Lipinski's Rule of Five: true

PROPERTIES

Physical Property

• Solubility: DMSO

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: B-Raf

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S1104

Research Area

• Description: Cancer

Biological Activity

• Description: GDC-0879 is a novel potent, selective B-Raf inhibitor for B-Raf^V600E with IC50 of 0.13 nM.
• Targets: B-Raf^V600E
• IC50: 0.13 nM ^[1]
• In Vitro: 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-Raf^V600E 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]
• 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 GDC-0879 administration. ^[2] Whereas GDC-0879-mediated efficacy is associated strictly with BRAF^V600E 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 BRAF^V600E melanoma cells to GDC-0879 could be dramatically altered by pharmacologic and genetic modulation of phosphatidylinositol 3-kinase pathway activity. ^[2]

Protocol

• Protocol: Animal Study ^[2]
• Animal Models: Female nu/nu mice
• Formulation: 0.5% methylcellulose/0.2% Tween 80
• Doses: 100 mg/kg
• Administration: Oral gavage

References

• References: [1] Wong H, et al. J Pharmacol Exp Ther. 2009, 329(1), 360-367.
• References: [2] Hoeflich KP, et al. Cancer Res. 2009, 69(7), 3042-3051.

REFERENCES

• Wong H, et al. J Pharmacol Exp Ther. 2009, 329(1), 360-367.
• Hoeflich KP, et al. Cancer Res. 2009, 69(7), 3042-3051.