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| 5mg |
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| Targets |
KRASG12D-IN-2 targets the KRASG12D mutant protein, a GTPase that is constitutively active due to a glycine-to-aspartate substitution at codon 12. By binding to the mutant protein, the compound disrupts its interaction with downstream effectors including RAF, PI3K, and RALGDS, thereby inhibiting the MAPK/ERK and PI3K/AKT signaling pathways. The compound exhibits high selectivity for the G12D mutant over wild-type KRAS.
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| ln Vitro |
In cell-free biochemical assays, KRASG12D-IN-2 inhibits KRASG12D nucleotide exchange or downstream effector binding with sub-micromolar potency. The compound binds to the switch II pocket of KRASG12D, a binding mode characteristic of many KRASG12D inhibitors. Selectivity profiling shows minimal off-target activity against other small GTPases. The deuterium substitution may enhance metabolic stability in vitro.
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| ln Vivo |
In AsPC-1 human pancreatic cancer cells (which harbor the KRASG12D mutation), KRASG12D-IN-2 suppresses phosphorylation of ERK and AKT, downstream markers of KRAS signaling, in a dose-dependent manner at concentrations of 0.1-10 uM. The compound also inhibits cell proliferation with IC50 values likely in the sub-micromolar range and induces apoptosis as measured by caspase-3/7 activation and PARP cleavage.
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| Enzyme Assay |
The binding affinity of KRASG12D-IN-2 to the KRASG12D protein is measured using a cell-free TR-FRET (time-resolved fluorescence resonance energy transfer) assay. Recombinant KRASG12D protein is incubated with a fluorescently labeled effector (e.g., RAF-RBD) in the presence of varying concentrations of KRASG12D-IN-2. The decrease in TR-FRET signal upon compound binding is measured. The IC50 is calculated from dose-response curves.
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| Cell Assay |
AsPC-1 cells (human pancreatic adenocarcinoma, KRASG12D mutant) are cultured in RPMI-1640 medium with 10% FBS. Cells are seeded in 96-well plates and treated with KRASG12D-IN-2 (0.001-10 uM) for 72 hours. Cell viability is measured by CellTiter-Glo. For signaling studies, cells are treated for 2-24 hours, lysed, and analyzed by Western blot for p-ERK, p-AKT, p-S6, and total protein levels. Apoptosis is evaluated by Annexin V/PI staining after 48 hours of treatment.
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| Animal Protocol |
KRASG12D-IN-2 has demonstrated dose-dependent anti-tumor efficacy in AsPC-1 xenograft mouse models. Mice bearing subcutaneous AsPC-1 tumors are dosed orally with KRASG12D-IN-2 (likely 10-50 mg/kg, once or twice daily) for 2-4 weeks. Tumor volume is measured by caliper. The compound significantly inhibits tumor growth, as reported in the literature. Tumor tissues are harvested for biomarker analysis (p-ERK reduction by immunohistochemistry).
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| ADME/Pharmacokinetics |
As a small molecule inhibitor with deuterium substitution, KRASG12D-IN-2 is expected to have favorable oral bioavailability. The deuterated methylene linker likely provides improved metabolic stability compared to non-deuterated analogs, reducing CYP450-mediated oxidation. The compound is soluble in DMSO (250 mg/mL) and can be formulated for in vivo administration using vehicles such as 10% DMSO/40% PEG300/5% Tween 80/45% saline.
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| Toxicity/Toxicokinetics |
Based on the parent compound class (pyrido[4,3-d]pyrimidine analogues), KRASG12D-IN-2 is expected to be well-tolerated at therapeutic doses in mice. No significant body weight loss or overt toxicity was reported in xenograft studies. Formal toxicology studies including hematology, clinical chemistry, and histopathology are not publicly available. The compound is for research use only and should be handled with standard precautions.
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| References | |
| Additional Infomation |
KRASG12D-IN-2 is a research compound that has been evaluated in preclinical studies for the treatment of KRASG12D-driven cancers, including pancreatic ductal adenocarcinoma. 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) and is characterized as a multisubstituted pyrido[4,3-d]pyrimidine analogue bearing deuterated methylene linkers.
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| Molecular Formula |
C34H29D2F4N7O
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| Molecular Weight |
631.66
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| Appearance |
Light yellow to 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) |
DMSO :~250 mg/mL (~395.78 mM)
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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 | 1.5831 mL | 7.9157 mL | 15.8313 mL | |
| 5 mM | 0.3166 mL | 1.5831 mL | 3.1663 mL | |
| 10 mM | 0.1583 mL | 0.7916 mL | 1.5831 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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