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| Targets |
EGFRL858R/T790M/C797S 18 nM (IC50)
EGFR-IN-11 targets the epidermal growth factor receptor (EGFR) tyrosine kinase, specifically the triple mutant EGFRL858R/T790M/C797S. This mutant form of EGFR is resistant to first-, second-, and third-generation EGFR-TKIs, including osimertinib. By inhibiting this mutant EGFR, EGFR-IN-11 overcomes acquired resistance to existing EGFR-TKIs. The compound inhibits EGFR phosphorylation, blocking downstream signaling pathways involved in cell proliferation and survival. |
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| ln Vitro |
EGFR-IN-11 (Compound D9; 0.0001-10 µM; 72 hours) exhibits a highly effective inhibitor of HCC827 and H1975 cell lines, with IC50 values of 0.88 nM and 0.20 µM, correspondingly[1]. EGFR-IN-11 (0.01 EGFR-IN-11 1 µM) inhibits the phosphorylation of EGFR in the HCC827, H1975, and A549 cell line in a concentration-dependent manner[1]. Potently inducing apoptosis in HCC827 cells, EGFR-IN-11 (1 µM; 24 h) also causes cell cycle arrests in HCC827 cells[1].
In vitro studies demonstrate that EGFR-IN-11 inhibits the triple mutant EGFRL858R/T790M/C797S with an IC50 of 18 nM. The compound exhibits anti-proliferative activity against HCC827, H1975, and A549 cells with IC50 values of 0.88 nM, 0.20 µM, and 2.91 µM, respectively. EGFR-IN-11 (0.01-1 µM) inhibits the phosphorylation of EGFR in HCC827, H1975, and A549 cell lines in a concentration-dependent manner. The compound induces apoptosis and arrests the cell cycle at G0/G1. |
| ln Vivo |
No detailed in vivo activity data has been published for EGFR-IN-11. The compound is a fourth-generation EGFR-TKI that has been characterized primarily in vitro. Its ability to inhibit the triple mutant EGFRL858R/T790M/C797S with high potency (IC50 = 18 nM) suggests that it could have potential for in vivo applications in treating osimertinib-resistant non-small cell lung cancer (NSCLC). Further studies would be needed to evaluate its efficacy in xenograft models and its pharmacokinetic and safety profile.
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| Enzyme Assay |
The EGFR kinase inhibitory activity of EGFR-IN-11 can be assessed using in vitro kinase assays. In a typical assay, recombinant EGFR kinase (wild-type or mutant) is incubated with a peptide substrate, ATP (including radiolabeled ³³P-ATP), and varying concentrations of EGFR-IN-11. The incorporation of phosphate into the substrate is measured, and the IC50 is calculated. The IC50 for the triple mutant EGFRL858R/T790M/C797S is 18 nM. The selectivity against other kinases can be assessed using kinase profiling services.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: Human lung cancer cell lines HCC827 (EGFRDel E746-A750), H1975 (EGFRL858R/T790M) and A549 (EGFRWT); epidermoid carcinoma cell line A431 (EGFRWT) Tested Concentrations: 0.0001, 0.0003, 0.001, 0.003, 0.01, 0.1, 1, 10 µM Incubation Duration: 72 hrs (hours) Experimental Results: Inhibited HCC827 H1975 A549 cells proliferation with IC50s of 0.88±0.09 nM, 0.20±0.01 μM, 2.91 ±0.61 μM, and >10 μM, respectively. Western Blot Analysis[1] Cell Types: HCC827, H1975 and A549 cells Tested Concentrations: 1.00, 0.10 and 0.01 µM for HCC827 cells; 10.00, 1.00 and 0.10 µM for H1975 and A549 cells Incubation Duration: 8 hrs (hours) Experimental Results: Suppressed EGFR phosphorylation in a concentration-dependent manner. EGFR phosphorylation in the HCC827 cell line was more remarkably suppressed than in the H1975 and A549 cell lines. Apoptosis Analysis[1] Cell Types: HCC827 cells Tested Concentrations: 1 µM Incubation Duration: 24 hrs (hours) Experimental Results: The percentages of apoptotic cells is 56.91%. Cell Cycle Analysis[1] Cell Types: HCC827 cells Concen The cellular activity of EGFR-IN-11 is assessed using NSCLC cell lines including HCC827, H1975, and A549 cells. Cells are seeded in 96-well plates and treated with escalating concentrations of EGFR-IN-11 (0.1 nM-10 µM). Cell viability is measured using MTT or CellTiter-Glo assays, and IC50 values are calculated. EGFR phosphorylation is assessed by Western blotting using phospho-specific antibodies for EGFR. Apoptosis is assessed by annexin V/propidium iodide staining or caspase activation assays. Cell cycle analysis is performed using flow cytometry. |
| Animal Protocol |
No detailed in vivo animal model data has been published for EGFR-IN-11. The compound has been primarily characterized in vitro as a research tool for studying EGFR mutant-driven cancers. Future studies may involve the use of mouse xenograft models of osimertinib-resistant NSCLC to assess the in vivo efficacy of EGFR-IN-11. The compound's ability to inhibit the triple mutant EGFR with high potency makes it a promising candidate for further development.
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| ADME/Pharmacokinetics |
EGFR-IN-11 is soluble in DMSO (112.5 mg/mL, 196.09 mM) and can be formulated for in vivo studies using 10% DMSO + 40% PEG300 + 5% Tween 80 + 45% Saline (4 mg/mL, 6.97 mM). The compound has a molecular weight of 573.71 and a molecular formula of C29H35N9O2S. It has a density of 1.48 g/cm³ (predicted). The compound is typically stored as a powder at -20°C for up to 3 years or in solvent at -80°C for 1 year.
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| Toxicity/Toxicokinetics |
No detailed toxicity data has been published for EGFR-IN-11. As a fourth-generation EGFR-TKI, the compound may have on-target effects on normal tissues expressing EGFR, such as skin and gastrointestinal epithelium. The compound's selectivity for the mutant EGFR over wild-type EGFR may contribute to a favorable safety profile. Comprehensive toxicology studies would be required to evaluate its safety profile for potential therapeutic development.
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| References | |
| Additional Infomation |
EGFR-IN-11 (CAS# 2463200-44-2) is a fourth-generation EGFR-tyrosine kinase inhibitor targeting the triple mutant EGFRL858R/T790M/C797S with an IC50 of 18 nM. It significantly suppresses EGFR phosphorylation, induces apoptosis, and arrests the cell cycle at G0/G1. The compound exhibits anti-proliferative activity against HCC827, H1975, and A549 cells with IC50 values of 0.88 nM, 0.20 µM, and 2.91 µM, respectively. The molecular formula is C29H35N9O2S and molecular weight is 573.71. EGFR-IN-11 is a research tool for studying EGFR mutant-driven cancers and overcoming acquired resistance to EGFR-TKIs.
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| Molecular Formula |
C29N9O2SH35
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|---|---|
| Molecular Weight |
573.7123
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| Exact Mass |
573.26
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| Elemental Analysis |
C, 60.71; H, 6.15; N, 21.97; O, 5.58; S, 5.59
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| CAS # |
2463200-44-2
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| PubChem CID |
145712397
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| Appearance |
White to yellow solid powder
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| LogP |
3.7
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
41
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| Complexity |
971
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| Defined Atom Stereocenter Count |
1
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| SMILES |
N1(CCN(C)CC1)C1C=CC(=CC=1)NC1=NC2N([C@@H]3CCN(C3)S(=O)(=O)C3CC3)C(NC3C=CC=CC=3)=NC=2C=N1
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| InChi Key |
RNEHWYIFHKBZAW-XMMPIXPASA-N
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| InChi Code |
InChI=1S/C29H35N9O2S/c1-35-15-17-36(18-16-35)23-9-7-22(8-10-23)31-28-30-19-26-27(34-28)38(29(33-26)32-21-5-3-2-4-6-21)24-13-14-37(20-24)41(39,40)25-11-12-25/h2-10,19,24-25H,11-18,20H2,1H3,(H,32,33)(H,30,31,34)/t24-/m1/s1
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| Chemical Name |
(R)-9-(1-(cyclopropylsulfonyl)pyrrolidin-3-yl)-N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine
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| Synonyms |
EGFR-IN-11; RXN00442; RXN-00442; RXN 00442;
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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 (217.88 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.63 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 (3.63 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7430 mL | 8.7152 mL | 17.4304 mL | |
| 5 mM | 0.3486 mL | 1.7430 mL | 3.4861 mL | |
| 10 mM | 0.1743 mL | 0.8715 mL | 1.7430 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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