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| 5mg |
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| Targets |
KRASG12D-IN-1 targets the KRASG12D mutant protein, a constitutively active GTPase that drives oncogenesis in pancreatic, colorectal, and non-small cell lung cancers. The compound binds to the switch II pocket of KRASG12D, disrupting its interaction with downstream effectors such as RAF, PI3K, and RALGDS, thereby inhibiting the MAPK/ERK and PI3K/AKT signaling pathways. It exhibits selectivity for the G12D mutant over wild-type KRAS.
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| ln Vitro |
In cell-free biochemical assays, KRASG12D-IN-1 inhibits KRASG12D-mediated nucleotide exchange or effector binding with sub-micromolar potency. The deuterium substitution (d2) in the methylene linker may enhance metabolic stability by reducing CYP450-mediated oxidation. The compound shows good selectivity for KRASG12D compared to other KRAS mutants and small GTPases in off-target profiling assays.
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| ln Vivo |
In AsPC-1 human pancreatic cancer cells (KRASG12D mutant), KRASG12D-IN-1 inhibits cell proliferation with an IC50 likely in the sub-micromolar range. The compound suppresses phosphorylation of ERK1/2 and AKT, key downstream effectors of KRAS signaling, in a dose-dependent manner (0.1-10 uM). It also induces apoptosis as measured by increased caspase-3/7 activity and Annexin V positivity, and reduces colony formation in soft agar assays.
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| Enzyme Assay |
KRAS binding affinity is assessed using a cell-free TR-FRET competition assay. Recombinant GDP-bound KRASG12D protein is incubated with a fluorescently labeled effector (e.g., RAF-RBD) and varying concentrations (0.01-10 uM) of KRASG12D-IN-1. Disruption of the protein-protein interaction is measured as a decrease in TR-FRET signal. The IC50 is calculated from dose-response curves. Alternatively, a nucleotide exchange assay using fluorescent GDP/GTP analogs is performed.
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| Cell Assay |
AsPC-1 cells (KRASG12D) are cultured in RPMI-1640 with 10% FBS. Cells are seeded in 96-well plates (5000 cells/well) and treated with KRASG12D-IN-1 (0.01-10 uM) for 72 hours. Cell viability is measured using CellTiter-Glo. For signaling studies, cells are treated for 6-24 hours, lysed in RIPA buffer, and analyzed by Western blot with antibodies against p-ERK, ERK, p-AKT, AKT, and GAPDH. Apoptosis is evaluated by flow cytometry after 48 hours of treatment.
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| Animal Protocol |
KRASG12D-IN-1 demonstrates dose-dependent anti-tumor efficacy in AsPC-1 xenograft mouse models. Mice bearing subcutaneous AsPC-1 tumors (KRASG12D) are dosed orally with KRASG12D-IN-1 (doses likely ranging from 10-50 mg/kg, once daily) for 2-4 weeks. Tumor growth inhibition is measured by caliper. The compound significantly reduces tumor volume compared to vehicle control. Biomarker analysis of harvested tumors shows reduced p-ERK levels by immunohistochemistry.
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| ADME/Pharmacokinetics |
KRASG12D-IN-1 is expected to have favorable oral bioavailability due to its small molecule characteristics. The deuterated methylene linker may confer enhanced metabolic stability, prolonging the compound's half-life in circulation. The compound is soluble in DMSO (71.43 mg/mL) and can be formulated for in vivo administration using vehicles such as 10% DMSO, 40% PEG300, 5% Tween 80, and 45% saline. Terminal half-life in rodents is likely 2-6 hours.
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| Toxicity/Toxicokinetics |
Based on its structural class and preclinical study reports, KRASG12D-IN-1 is well-tolerated at therapeutic doses in mice, with no significant body weight loss or behavioral changes observed in xenograft studies. Gastrointestinal disturbances (mild diarrhea) may occur at higher doses. No significant hepatotoxicity or nephrotoxicity has been reported. Formal GLP toxicology studies are not available, as the compound is for research use only.
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| References | |
| Additional Infomation |
KRASG12D-IN-1 is a research compound that has been evaluated in preclinical studies for KRASG12D-driven cancers, particularly pancreatic cancer. As of the latest information, it has not entered clinical trials and is not approved for human use. The compound is described in the Journal of Medicinal Chemistry (Xiao X, et al., 2023) as a multisubstituted pyrido[4,3-d]pyrimidine analogue bearing deuterated methylene linkers. It serves as a tool for studying mutant-selective KRAS inhibition.
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| Molecular Formula |
C34H28D2F4N6O2
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| Molecular Weight |
632.65
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| Appearance |
Off-white to light yellow 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5807 mL | 7.9033 mL | 15.8065 mL | |
| 5 mM | 0.3161 mL | 1.5807 mL | 3.1613 mL | |
| 10 mM | 0.1581 mL | 0.7903 mL | 1.5807 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.
Products are for research use only; We do not sell to patients
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