2. GPCR/G Protein MAPK/ERK Pathway
  3. Ras
  4. MRTX1133 formic

MRTX1133 formic is a noncovalent, potent, and selective KRAS G12D inhibitor. MRTX1133 formic optimally fills the switch II pocket and extends three substituents to favorably interact with the protein, resulting in an estimated KD against KRAS G12D of 0.2 pM. MRTX1133 formic prevents SOS1-catalyzed nucleotide exchange and/or formation of the KRASG12D/GTP/RAF1 complex, thereby inhibiting mutant KRAS-dependent signal transduction. MRTX1133 formic shows efficacy in tumor models harboring KRAS G12D mutations.

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MRTX1133 formic Chemical Structure

MRTX1133 formic Chemical Structure

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Other Forms of MRTX1133 formic:

Top Publications Citing Use of Products

    MRTX1133 formic purchased from MedChemExpress. Usage Cited in: Cancer Discov. 2024 Jul 3.  [Abstract]

    MRTX1133 (0.5 μM; 24 h)-treated 9805 cells produce conditioned medium (CM) that induces a reduction in Il33 expression in CD1WT fibroblasts.

    MRTX1133 formic purchased from MedChemExpress. Usage Cited in: Immunity. 2023 Nov 14;56(11):2570-2583.e6.  [Abstract]

    Western blot showing phosphorylated and total ERK1/2 in lysates of KRASG12D-mutated A427 cells, treated with anti-KRASG12D-IgA1 or MRTX1133.

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    Description

    MRTX1133 formic is a noncovalent, potent, and selective KRAS G12D inhibitor. MRTX1133 formic optimally fills the switch II pocket and extends three substituents to favorably interact with the protein, resulting in an estimated KD against KRAS G12D of 0.2 pM. MRTX1133 formic prevents SOS1-catalyzed nucleotide exchange and/or formation of the KRASG12D/GTP/RAF1 complex, thereby inhibiting mutant KRAS-dependent signal transduction. MRTX1133 formic shows efficacy in tumor models harboring KRAS G12D mutations[1][2].

    IC50 & Target[1]

    KRas G12D

    0.2 pM (Kd)

    In Vitro

    MRTX1133 formic inhibits ERK phosphorylation in the AGS cell line with an IC50 ranging 1-10 nM (AsPC-1, Panc 04.03, Panc 02.03, SW1990, GP2D, Suit2, A427, SNU1033, and HPAC cells). In a 2D viability assay, the IC50 of MRTX1133 formic is 6 nM against AGS cells (KRAS G12D), while demonstrating more than 500-fold selectivity against MKN1, a cell line which is dependent on KRAS for its growth and survival due to the amplification of wild-type KRAS[1].

    MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
    In Vivo

    MRTX1133 formic displays efficacious in a KRAS G12D mutant xenograft mouse tumor model[1].

    MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Model: 6-8-weekold, female, athymic nude-Foxn1nu mice (Panc 04.03 model)[1]
    Dosage: 3, 10, or 30 mg/kg
    Administration: Intraperitoneal; twice a day for 28 days
    Result: Resulted in a dose-dependent antitumor activity with 94% growth inhibition observed at 3 mg/kg BID (IP) and tumor regressions of -62% and -73% observed at 10 and 30 mg/kg BID (IP), respectively.
    Molecular Weight

    646.66

    Formula

    C34H33F3N6O4
    Appearance

    Solid

    Color

    Yellow to khaki

    SMILES

    O=CO.OC1=CC(C2=C(F)C3=NC(OC[C@]45C[C@@H](F)CN4CCC5)=NC(N6C[C@H]7N[C@H](CC7)C6)=C3C=N2)=C8C(C#C)=C(F)C=CC8=C1
    Shipping

    Room temperature in continental US; may vary elsewhere.
    Storage

    4°C, sealed storage, away from moisture

    *In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)

    Solvent & Solubility
    In Vitro: 

    DMSO : 50 mg/mL (77.32 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

    H2O : 25 mg/mL (38.66 mM; ultrasonic and warming and heat to 60°C)

    Preparing
    Stock Solutions
    Concentration Solvent Mass 1 mg 5 mg 10 mg
    1 mM 1.5464 mL 7.7320 mL 15.4641 mL
    5 mM 0.3093 mL 1.5464 mL 3.0928 mL
    View the Complete Stock Solution Preparation Table

    * Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
    Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture). When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

    * Note: If you choose water as the stock solution, please dilute it to the working solution, then filter and sterilize it with a 0.22 μm filter before use.

    • Molarity Calculator

    • Dilution Calculator

    Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

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    Concentration (start) × Volume (start) = Concentration (final) × Volume (final)

    This equation is commonly abbreviated as: C1V1 = C2V2

    Concentration (start)

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    In Vivo:

    Select the appropriate dissolution method based on your experimental animal and administration route.

    For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
    To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day.
    The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

    • Protocol 1

      Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% Saline

      Solubility: ≥ 2.08 mg/mL (3.22 mM); Clear solution

      This protocol yields a clear solution of ≥ 2.08 mg/mL (saturation unknown).

      Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (20.8 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.

      Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
    • Protocol 2

      Add each solvent one by one:  10% DMSO    90% (20% SBE-β-CD in Saline)

      Solubility: ≥ 2.08 mg/mL (3.22 mM); Clear solution

      This protocol yields a clear solution of ≥ 2.08 mg/mL (saturation unknown).

      Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (20.8 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.

      Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
    In Vivo Dissolution Calculator
    Please enter the basic information of animal experiments:

    Dosage

    mg/kg

    Animal weight
    (per animal)

    g

    Dosing volume
    (per animal)

    μL

    Number of animals

    Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
    Purity & Documentation
    References

    Complete Stock Solution Preparation Table

    * Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
    Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture). When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

    Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
    H2O / DMSO 1 mM 1.5464 mL 7.7320 mL 15.4641 mL 38.6602 mL
    5 mM 0.3093 mL 1.5464 mL 3.0928 mL 7.7320 mL
    10 mM 0.1546 mL 0.7732 mL 1.5464 mL 3.8660 mL
    15 mM 0.1031 mL 0.5155 mL 1.0309 mL 2.5773 mL
    20 mM 0.0773 mL 0.3866 mL 0.7732 mL 1.9330 mL
    25 mM 0.0619 mL 0.3093 mL 0.6186 mL 1.5464 mL
    30 mM 0.0515 mL 0.2577 mL 0.5155 mL 1.2887 mL
    DMSO 40 mM 0.0387 mL 0.1933 mL 0.3866 mL 0.9665 mL
    50 mM 0.0309 mL 0.1546 mL 0.3093 mL 0.7732 mL
    60 mM 0.0258 mL 0.1289 mL 0.2577 mL 0.6443 mL

    * Note: If you choose water as the stock solution, please dilute it to the working solution, then filter and sterilize it with a 0.22 μm filter before use.

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    MRTX1133 formic Related Classifications

    Keywords:

    MRTX1133MRTX 1133MRTX-1133Rasfirst-in-classactiveinactivestatesmutantwild-typetumorcellsInhibitorinhibitorinhibit

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