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    ARS-853
    ARS-853

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V2745
    CAS #: 1629268-00-3Purity ≥98%

    Description: ARS-853 is a  novel, potent, selective, and covalent inhibitor of KRAS(G12C) with IC50 of 2.5 μM. 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.

    References:  2016 Mar;6(3):316-29;  2016 Feb 5;351(6273):604-8.


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    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


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    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
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    Formulation & Dosage
    References  2016 Mar;6(3):316-29


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    ARS-853


    Identification of a covalent KRASG12C inhibitor active in cells.  2016 Mar;6(3):316-29

     ARS-853


    Proteomic cysteine profiling of ARS-853 selectivity.  2016 Mar;6(3):316-29

     ARS-853


    Cellular activity and selectivity of ARS-853.   2016 Mar;6(3):316-29

    ARS-853

     ARS-853


    Cellular activity and selectivity of ARS-853.  2016 Mar;6(3):316-29

     ARS-853


    The kinetics of cellular G12C engagement and signaling inhibition with a GDP-state selective inhibitor demonstrates rapid nucleotide cycling of KRASG12C between GTP- and GDP-bound states.   2016 Mar;6(3):316-29

     ARS-853


    Modulation of KRASG12C activity alters ARS-853 target engagement and supports novel therapeutic strategies for targeting KRAS.  2016 Mar;6(3):316-29


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