| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| Other Sizes |
| Targets |
KRASG12C (mutant GTPase KRAS with a glycine-to-cysteine mutation at codon 12). As the inactive isomer, (3R,10R,14aS)-AZD4625 binds to the KRASG12C protein with significantly lower affinity compared to the active isomer. It does not covalently modify the mutant cysteine residue and therefore fails to lock KRAS in its inactive GDP-bound state.
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|---|---|
| ln Vitro |
As an inactive control compound, (3R,10R,14aS)-AZD4625 shows no significant inhibition of KRASG12C activity in biochemical assays. Its IC50 for KRASG12C inhibition is orders of magnitude higher than that of the active AZD4625 (IC50 = 3 nM). In cellular assays, the isomer does not inhibit the MAPK pathway (no reduction of pCRAF, pMEK, pERK) nor the PI3K pathway (no reduction of pAKT, pS6). It does not induce cell apoptosis.
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| ln Vivo |
In mouse xenograft models, (3R,10R,14aS)-AZD4625 does not produce any anti-tumor activity. It serves as a negative control in efficacy studies to demonstrate that the observed tumor growth inhibition of the active AZD4625 is target-specific and stereospecific. No reduction in tumor volume or suppression of downstream signaling is observed.
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| Enzyme Assay |
A KRASG12C biochemical inhibition assay is performed using purified GDP-bound KRASG12C protein. The compound is incubated with the protein for 1-2 hours at room temperature to allow for covalent binding. Then, an excess of a fluorescently-labeled probe that binds to the switch-II pocket is added. The fluorescence signal is measured to determine binding. Alternatively, mass spectrometry is used to confirm covalent modification.
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| Cell Assay |
Human cancer cell lines harboring the KRASG12C mutation (e.g., NCI-H358, MIA PaCa-2) are seeded in 96-well plates and treated with various concentrations of the isomer or the active compound for 72-120 hours. Cell viability is measured using the CellTiter-Glo assay. ERK phosphorylation (pERK) is assessed by Western blot or AlphaLISA. Apoptosis is measured by caspase-3/7 activity.
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| Animal Protocol |
Female BALB/c nude mice bearing subcutaneous KRASG12C mutant xenografts (e.g., NCI-H358 lung cancer model) are administered the isomer via oral gavage at matched doses (e.g., 10-100 mg/kg) daily for 14-28 days. Tumor volumes are measured by calipers twice weekly. Tumor tissues are collected at endpoint for analysis of pERK and cleaved caspase-3. No tumor growth inhibition (TGI) is observed.
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| ADME/Pharmacokinetics |
Although the (3R,10R,14aS)-isomer has identical physicochemical properties to the active AZD4625, it is not intended for in vivo dosing. The active AZD4625 demonstrates high oral bioavailability (F% > 70%) in preclinical species, low to moderate plasma clearance, and a half-life suitable for once- or twice-daily dosing. It distributes well to tumor tissues. The isomer shows similar absorption but no target engagement.
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| Toxicity/Toxicokinetics |
The inactive isomer is non-toxic at concentrations used for control experiments. The active AZD4625 has been shown to be well tolerated in preclinical models. In chronic daily dosing studies, AZD4625 produced no significant body weight loss or overt signs of toxicity. The most common adverse events expected in humans would be rash, gastrointestinal disturbances, and fatigue, consistent with other KRASG12C inhibitors.
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| References |
[1]. Kettle JG, et al. Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C. J Med Chem. 2022 May 12;65(9):6940-6952.
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| Additional Infomation |
(3R,10R,14aS)-AZD4625 is a research-grade chemical used exclusively as a negative control to validate mechanism-of-action studies targeting KRASG12C. The active enantiomer AZD4625 (Compound 21) is a clinical development candidate discovered by AstraZeneca. A Phase 1 clinical trial (NCT05132075) has evaluated AZD4625 in patients with KRASG12C mutant solid tumors. This product is for research use only and is not FDA-approved.
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| Molecular Formula |
C24H21CLF2N4O3
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|---|---|
| Molecular Weight |
486.90
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| Related CAS # |
AZD4625
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| Appearance |
White to off-white solid powder
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO :~125 mg/mL (~256.73 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.27 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (4.27 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: 2.08 mg/mL (4.27 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0538 mL | 10.2690 mL | 20.5381 mL | |
| 5 mM | 0.4108 mL | 2.0538 mL | 4.1076 mL | |
| 10 mM | 0.2054 mL | 1.0269 mL | 2.0538 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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