Adagrasib [2326521-71-3]

Référence HY-130149-10mg

Conditionnement : 10mg

Marque : MedChemExpress

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Adagrasib (MRTX849) is a potent, orally-available, and mutation-selective covalent inhibitor of KRAS G12C with potential antineoplastic activity. Adagrasib covalently binds to KRAS G12C at the cysteine at residue 12, locks the protein in its inactive GDP-bound conformation, and inhibits KRAS-dependent signal transduction.

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Adagrasib Chemical Structure

Adagrasib Chemical Structure

CAS No. : 2326521-71-3

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Based on 21 publication(s) in Google Scholar

Other Forms of Adagrasib:

  • MRTX849 analog 24 In-stock
  • LC-2 In-stock

    Adagrasib purchased from MedChemExpress. Usage Cited in: bioRxiv. 2023 Feb 18.

    Adagrasib (MRTX849; 60 nM-1 µM) induces Fas expression in KrasG12C mutant MIA PaCa-2 cells.

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    Description

    Adagrasib (MRTX849) is a potent, orally-available, and mutation-selective covalent inhibitor of KRAS G12C with potential antineoplastic activity. Adagrasib covalently binds to KRAS G12C at the cysteine at residue 12, locks the protein in its inactive GDP-bound conformation, and inhibits KRAS-dependent signal transduction[1][2].

    IC50 & Target

    KRas G12C

     

    In Vitro

    Adagrasib (MRTX849) (0.1-10000 nM; 3-day/2D conditions; 12-day/3D conditions) potently inhibits cell growth in the vast majority of KRAS G12C-mutant cell lines with IC50s ranging between 10 and 973 nM in the 2D format and between 0.2 and 1042 nM in the 3D format[1].
    Adagrasib (0.24-1000 nM; 24 hours) inhibits KRAS-dependent signaling targets including ERK1/2 phosphorylation (Thr202/Tyr204 ERK1; pERK), S6 phosphorylation (RSK-dependent Ser235/236; pS6) and expression of the ERK-regulated DUSP6[1].

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

    Cell Viability Assay[1]

    Cell Line: MIA PaCa-2, H1373, H358, H2122, SW1573, H2030, KYSE-410 cells (G12C); H1299 (WT); A549 (G12S), HCT116 (G13D) cells
    Concentration: 0.1, 1, 10, 100, 1000, 10000 nM
    Incubation Time: 24 hours
    Result: Inhibits cell growth in the vast majority of KRAS G12C-mutant cell lines with IC50 values ranging between 10 and 973 nM in the 2D format and between 0.2 and 1042 nM in the 3D format.

    Western Blot Analysis[1]

    Cell Line: MIA PaCa-2 cells
    Concentration: 0.24, 0.5, 1.0, 2.0, 3.9, 7.8, 15.6, 31.3, 62.5, 125, 250, 500, 1000 nM
    Incubation Time: 24 hours
    Result: Inhibits KRAS-dependent signaling targets including ERK1/2 phosphorylation (Thr202/Tyr204 ERK1; pERK), S6 phosphorylation (RSK-dependent Ser235/236; pS6) and expression of the ERK-regulated DUSP6, each with IC50s in the single-digit nanomolar range in cell lines.
    In Vivo

    Adagrasib (1-100 mg/kg; i.g.; daily until day 16) demonstrates dose-dependent anti-tumor efficacy over a well-tolerated dose range, and the maximally efficacious dose of MRTX849 is between 30-100 mg/kg/day[1].

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

    Animal Model: MIA PaCa-2 model (6-8-week-old, female, athymic nude-Foxn1 nu mice)[1]
    Dosage: 1, 3, 10, 30 and 100 mg/kg
    Administration: Oral gavage; daily until Day 16
    Result: Rapid tumor regression was observed at the earliest posttreatment tumor measurement and animals in the 30 and 100 mg/kg cohorts exhibited evidence of a complete response at study Day 15. Dosing was stopped at study Day 16 and all 4 mice in the 100 mg/kg cohort and 2 out of 7 mice in the 30 mg/kg cohort remained tumor-free through study Day 70.
    Essai clinique
    Masse moléculaire

    604.12

    Formule

    C32H35ClFN7O2

    CAS No.

    2326521-71-3

    Appearance

    Solid

    Color

    White to yellow

    SMILES

    N#CC[C@@H]1N(C(C(F)=C)=O)CCN(C2=C3C(CN(C4=C5C(Cl)=CC=CC5=CC=C4)CC3)=NC(OC[C@H]6N(C)CCC6)=N2)C1

    Livraison

    Room temperature in continental US; may vary elsewhere.

    Stockage
    Powder -20°C 3 years
    4°C 2 years
    In solvent -80°C 6 months
    -20°C 1 month
    Solvant et solubilité
    In Vitro: 

    DMSO : 25 mg/mL (41.38 mM; ultrasonic and warming and heat to 60°C; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

    Preparing
    Stock Solutions
    Concentration Solvent Mass 1 mg 5 mg 10 mg
    1 mM 1.6553 mL 8.2765 mL 16.5530 mL
    5 mM 0.3311 mL 1.6553 mL 3.3106 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. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

    • Calculateur de molarité

    • Calculateur de dilution

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

    Mass
    =
    Concentration
    ×
    Volume
    ×
    Molecular Weight *

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

    This equation is commonly abbreviated as: C1V1 = C2V2

    Concentration (start)

    C1

    ×
    Volume (start)

    V1

    =
    Concentration (final)

    C2

    ×
    Volume (final)

    V2

    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:  5% DMSO    40% PEG300    5% Tween-80    50% Saline

      Solubility: ≥ 2.62 mg/mL (4.34 mM); Clear solution

    • Protocol 2

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

      Solubility: ≥ 2.5 mg/mL (4.14 mM); Clear solution

      This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).

      Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 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.
    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.
    Please enter your animal formula composition:
    %
    DMSO +
    +
    %
    Tween-80 +
    %
    Saline
    Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
    The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
    Calculation results:
    Working solution concentration: mg/mL
    Method for preparing stock solution: mg drug dissolved in μL  DMSO (Stock solution concentration: mg/mL).
    The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
    Method for preparing in vivo working solution for animal experiments: Take μL DMSO stock solution, add μL . μL , mix evenly, next add μL Tween 80, mix evenly, then add μL Saline.
     If the continuous dosing period exceeds half a month, please choose this protocol carefully.
    Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
    Pureté et documentation

    Purity: 99.93%

    Références
    • [1]. Christensen JG, et al. The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients. Cancer Discov. 2019 Oct 28. pii: CD-19-1167.  [Content Brief]

      [2]. Kyriakos P. Papadopoulos, et al. A phase I/II multiple expansion cohort trial of MRTX849 in patients with advanced solid tumors with KRAS G12C mutation. Journal of Clinical Oncology 2019 37:15_suppl, TPS3161-TPS3161.

      [3]. Fell JB, Fischer JP, Baer BR, et al. Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer. J Med Chem. 2020;63(13):6679-6693.  [Content Brief]

      [4]. Awad MM, Liu S, Rybkin II, et al. Acquired Resistance to KRASG12C Inhibition in Cancer. N Engl J Med. 2021;384(25):2382-2393.  [Content Brief]

    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. 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
    DMSO 1 mM 1.6553 mL 8.2765 mL 16.5530 mL 41.3825 mL
    5 mM 0.3311 mL 1.6553 mL 3.3106 mL 8.2765 mL
    10 mM 0.1655 mL 0.8277 mL 1.6553 mL 4.1383 mL
    15 mM 0.1104 mL 0.5518 mL 1.1035 mL 2.7588 mL
    20 mM 0.0828 mL 0.4138 mL 0.8277 mL 2.0691 mL
    25 mM 0.0662 mL 0.3311 mL 0.6621 mL 1.6553 mL
    30 mM 0.0552 mL 0.2759 mL 0.5518 mL 1.3794 mL
    40 mM 0.0414 mL 0.2069 mL 0.4138 mL 1.0346 mL
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    Adagrasib Related Classifications

    Help & FAQs

    Keywords:

    Adagrasib2326521-71-3MRTX849MRTX 849MRTX-849RasKRASG12Cselectivecovalentanti-tumorGDP-boundstateinactiveMIA PaCa-2H1373cellsmutantInhibitorinhibitorinhibit

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