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| Targets |
The primary target of NRC-2694 is the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase that is frequently mutated or overexpressed in many tumor cell types. EGFR plays a key role in tumor cell proliferation and tumor vascularization. NRC-2694 acts as an antagonist of EGFR, binding to and inhibiting the receptor. The compound targets the tyrosine kinase domain of the receptor, preventing its activation and subsequent downstream signaling. By inhibiting EGFR, NRC-2694 prevents EGFR-mediated signaling, which leads to cell death in EGFR-expressing tumor cells. EGFR is a well-validated therapeutic target for various malignancies, and its inhibition is a clinically proven strategy for cancer treatment.
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| ln Vitro |
Similar suppression of EGFR expression was induced by NRC-2694 at a dose of 80 ng (190 nm) [1].
In vitro, NRC-2694 exhibits significant anti-cancer and anti-proliferative activity. The compound inhibits the proliferation of cancer cells that express EGFR, including H1299 and A549 cells, which are commonly used models for non-small cell lung cancer. The in vitro invasiveness of these cells is reduced in the presence of various concentrations of NRC-2694, indicating that the compound not only inhibits cell proliferation but also impedes the invasive capacity of cancer cells. The compound's mechanism of action involves binding to the tyrosine kinase domain of EGFR, preventing its activation and subsequent downstream signaling events that drive cell proliferation and survival. NRC-2694's anti-proliferative effects are consistent with its role as an EGFR antagonist, and its activity can be quantified using standard cell viability assays such as MTT, CellTiter-Glo, or colony formation assays. The compound's ability to inhibit cell invasion suggests that it may also have anti-metastatic potential, a critical consideration for cancer therapeutics. |
| ln Vivo |
NRC-2694's maximum tolerated dose in toxicity tests was 2000 mg/kg (po) for both male and female mice. In mice, NRC-2694 (10 mg/kg) causes tumor regression [1].
In vivo, NRC-2694 is orally bioavailable and has potential antineoplastic activity. Upon oral administration, the compound binds to and inhibits EGFR, which prevents EGFR-mediated signaling and leads to cell death in EGFR-expressing tumor cells. The compound's oral bioavailability is a significant advantage, as it enables convenient dosing regimens and improves patient compliance compared to intravenously administered therapeutics. The inhibition of EGFR by NRC-2694 is expected to result in reduced tumor growth, decreased angiogenesis, and increased apoptosis in EGFR-driven tumors. While specific in vivo efficacy data for NRC-2694 are not extensively detailed in the available literature, its mechanism of action and in vitro activity suggest that it would be effective in xenograft models of EGFR-dependent cancers, such as non-small cell lung cancer, head and neck squamous cell carcinoma, and colorectal cancer. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for NRC-2694 involve kinase activity assays using purified EGFR enzyme or cell lysates. The compound's inhibitory activity is measured by monitoring the phosphorylation of a substrate peptide or protein in the presence of ATP. IC50 values are determined from dose-response curves generated by plotting inhibitor concentration against residual kinase activity. These assays confirm that NRC-2694 directly inhibits EGFR kinase activity and provide quantitative measures of its potency. Selectivity profiling against a panel of other kinases can be performed to assess the compound's specificity for EGFR and to identify potential off-target effects. Binding assays using surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) can be employed to measure the affinity of NRC-2694 for EGFR and to confirm its binding to the tyrosine kinase domain.
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| Cell Assay |
In vitro cellular assays for NRC-2694 are conducted in cancer cell lines that express EGFR, such as H1299 and A549 non-small cell lung cancer cells. Cells are treated with varying concentrations of NRC-2694, and cell proliferation is measured using assays such as MTT, CellTiter-Glo, or colony formation assays. The in vitro invasiveness of cells is assessed using Transwell or Boyden chamber assays, where cells are allowed to migrate through a matrix-coated membrane in the presence of the compound. Apoptosis can be evaluated by measuring caspase activation, annexin V staining, or PARP cleavage. EGFR phosphorylation and downstream signaling (e.g., AKT, ERK) are assessed by western blotting using phospho-specific antibodies. These assays confirm that NRC-2694 engages its target in a cellular context and produces the expected anti-proliferative and pro-apoptotic effects.
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| Animal Protocol |
In vivo animal studies for NRC-2694 would typically be conducted in mouse xenograft models using human cancer cell lines that express EGFR, such as H1299, A549, or other EGFR-dependent tumor models. Animals would be administered the compound orally, and tumor growth inhibition would be monitored over time by caliper measurements. The compound's effects on EGFR signaling in tumors could be assessed by immunohistochemistry or western blotting of tumor tissue for phosphorylated EGFR and downstream effectors. Pharmacokinetic studies would be performed to determine the compound's oral bioavailability, half-life, and tissue distribution. Tumor vascularization could be assessed by immunohistochemistry for CD31 or other endothelial markers to evaluate the anti-angiogenic effects of EGFR inhibition.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of NRC-2694 indicate that it has a molecular weight of 418.49 and a molecular formula of C24H26N4O3. The compound is orally bioavailable, enabling convenient administration for in vivo studies. It is soluble in DMSO, facilitating its use in in vitro assays and formulation for in vivo administration. The compound's purity is typically >98% (HPLC), ensuring high quality and reproducibility in experimental studies. The compound contains an Alkyne group, which enables its use in click chemistry applications. For storage, the powder should be kept under appropriate conditions to maintain stability. The compound's physicochemical properties suggest that it has drug-like characteristics, including a molecular weight below 500 Da, which is generally favorable for oral bioavailability.
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| Toxicity/Toxicokinetics |
The toxicological profile of NRC-2694 is primarily derived from its use as a research compound in preclinical studies. As an EGFR inhibitor, potential on-target toxicities include skin rash, diarrhea, and interstitial lung disease, which are well-documented class effects of EGFR-targeted therapeutics. These toxicities arise from the physiological role of EGFR in maintaining epithelial barrier function and tissue homeostasis. Off-target effects would need to be assessed through broad selectivity profiling against other kinases and receptors. Standard toxicology studies, including acute and repeated-dose toxicity in rodents and non-rodent species, genotoxicity assessments, and cardiovascular safety evaluations, would be necessary to establish the compound's safety profile for clinical development. The compound's oral bioavailability and mechanism of action suggest that it could be developed as an anti-cancer therapeutic, but comprehensive toxicological evaluation would be required.
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| References | |
| Additional Infomation |
NRC-2694, an EGFR inhibitor, is a small molecule inhibitor of epidermal growth factor receptor (EGFR) with high oral bioavailability and potential anti-tumor activity. After oral administration, NRC-2694 binds to EGFR and inhibits its activity, thereby blocking EGFR-mediated signaling and ultimately leading to the death of EGFR-expressing tumor cells. EGFR is a receptor tyrosine kinase that is mutated in various tumor cell types and plays a crucial role in tumor cell proliferation and tumor angiogenesis.
NRC-2694 is an orally bioavailable EGFR inhibitor with potential antineoplastic activity. It is also known as EGFR Inhibitor NRC-2694. The compound binds to and inhibits EGFR, preventing EGFR-mediated signaling and leading to cell death in EGFR-expressing tumor cells. NRC-2694 exhibits anti-cancer and anti-proliferative properties. It is also a click chemistry reagent containing an Alkyne group, capable of undergoing copper-catalyzed azide-alkyne cycloaddition (CuAAc). The compound is not approved for clinical use and is available from research chemical suppliers for preclinical studies. Its dual functionality as both an EGFR inhibitor and a click chemistry reagent makes it a versatile tool for cancer research and chemical biology applications. |
| Molecular Formula |
C24H26N4O3
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|---|---|
| Molecular Weight |
418.497
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| Exact Mass |
418.2
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| CAS # |
936446-61-6
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| PubChem CID |
16129168
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
597.6±50.0 °C at 760 mmHg
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| Flash Point |
315.2±30.1 °C
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| Vapour Pressure |
0.0±1.7 mmHg at 25°C
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| Index of Refraction |
1.646
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| LogP |
2.84
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
31
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| Complexity |
591
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
WBKHQQZRHCECKK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H26N4O3/c1-3-18-6-4-7-19(14-18)27-24-20-15-23(22(29-2)16-21(20)25-17-26-24)31-11-5-8-28-9-12-30-13-10-28/h1,4,6-7,14-17H,5,8-13H2,2H3,(H,25,26,27)
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| Chemical Name |
N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine
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| Synonyms |
NRC2694; NRC 2694; NRC-2694
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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 (~597.39 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.97 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 (4.97 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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 (4.97 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3895 mL | 11.9474 mL | 23.8949 mL | |
| 5 mM | 0.4779 mL | 2.3895 mL | 4.7790 mL | |
| 10 mM | 0.2389 mL | 1.1947 mL | 2.3895 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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