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ARS-853
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
ARS-853图片
CAS NO:1629268-00-3
规格:≥98%
包装与价格:
包装价格(元)
1mg电议
2mg电议
5mg电议
10mg电议
25mg电议
50mg电议

产品介绍
理化性质和储存条件
Molecular Weight (MW) 432.94
Formula C22H29ClN4O3
CAS No. 1629268-00-3
Storage-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)DMSO: 85 mg/mL
Water: < 1 mg/mL
Ethanol: < 1 mg/mL
Chemical Name 2-Propen-1-one, 1-[3-[4-[2-[[4-chloro-2-hydroxy-5-(1-methylcyclopropyl)phenyl]amino]acetyl]-1- piperazinyl]-1-azetidinyl]-
Synonyms ARS853, ARS-853, ARS 853
SMILES Code C=CC(N1CC(N2CCN(C(CNC3=CC(C4(C)CC4)=C(Cl)C=C3O)=O)CC2)C1)=O
实验参考方法
In Vitro

In vitro activity: ARS-853 is a novel, potent, selective, covalent inhibitor of KRAS(G12C). It inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation. KRAS gain-of-function mutations occur in approximately 30% of all human cancers. To date, no targeted therapy has been discovered for cancers with KRAS mutations. Based on the rates of engagement and inhibition observed for ARS-853, along with a mutant-specific mass spectrometry-based assay for assessing KRAS activation status, the nucleotide state of KRAS(G12C) is in a state of dynamic flux that can be modulated by upstream signaling factors. These studies provide convincing evidence that the KRAS(G12C) mutation generates a 'hyperexcitable' rather than a 'statically active' state and that targeting the inactive, GDP-bound form is a promising approach for generating novel anti-RAS therapeutics.


Kinase Assay: GDP-loaded, hexahistidine-tagged, truncated (1-169) KRAS proteins (G12C, WT, G13D, as indicated) at 2 μmol/L final concentration were incubated with the test compounds at the doses and time points indicated in a buffer containing 20 mmol/L HEPES pH 7.5, 150 mmol/L NaCl, 1 mmol/L MgCl2, and 1 mmol/L DTT. Reactions were quenched by adding formic acid to 0.2%. The extent of covalent modification was determined by liquid chromatography, electrospray mass spectrometry analysis of the intact proteins on either a time of flight (TOF; Agilent 6530) or Q-Exactive (Thermo) mass spectrometer.


Cell Assay: Cells (35 × 103) adhered overnight were treated with compound at the indicated concentration and incubation time. After treatment, cells were washed twice with PBS buffer, and proteins were extracted using a buffer containing 9 mol/L urea, 10 mmol/L DTT, and 50 mmol/L ammonium bicarbonate, pH 8. Following iodoacetamide alkylation and trypsin digestion, the samples were analyzed by targeted LC/MS-MS analysis on a Dionex RSLCnano LC (Thermo Scientific) coupled with a Q-Exactive quadrupole orbitrap mass spectrometer (Thermo Scientific). Detailed descriptions of the sample processing and LC/MS-MS methods can be found in Supplementary Methods and Supplementary Table S6. KRASG12C mutant cells (H358) were treated with ARS853 for 5 hours. The effect on the level of active, or GTP-bound, KRAS was determined by a RAS-binding domain pull-down (RBD:PD) assay and immunoblotting with a KRAS-specific antibody.

In Vivo
Animal model
Formulation & Dosage
References Cancer Discov. 2016 Mar;6(3):316-29