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| Targets |
(Rac)-JBJ-04-125-02 targets the epidermal growth factor receptor (EGFR), specifically binding to an allosteric site located at the dimerization interface of the kinase domain. Unlike ATP-competitive inhibitors, this compound binds to the inactive conformation of EGFR, preventing its activation. It exhibits selectivity for the T790M/L858R mutant form of EGFR, which is the primary cause of resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). Its mechanism involves trapping the kinase in an inactive state, ultimately leading to tumor cell death.
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| ln Vitro |
In vitro, (Rac)-JBJ-04-125-02 is a potent, ATP-noncompetitive, and T790M/L858R-selective inhibitor of EGFR. It effectively inhibits cell proliferation as a single agent in NSCLC cell lines harboring the relevant mutations. Molecular dynamics simulations have revealed the detailed inhibitory mechanism of this compound as a potent EGFR inhibitor. It demonstrates selectivity for mutant EGFR over the wild-type receptor, reducing the risk of off-target toxicities. Specific IC50 values are not detailed in the search results.
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| ln Vivo |
In vivo, (Rac)-JBJ-04-125-02 has demonstrated efficacy as a single-agent inhibitor in preclinical models of mutant NSCLC. The compound is under investigation as a fourth-generation EGFR inhibitor to combat drug resistance associated with non-small cell lung cancer. The negative regulation mechanism of the compound has been partially clarified, although further studies are ongoing. Specific dosing regimens, tumor growth inhibition percentages, and animal model details are not provided in the search results.
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| Enzyme Assay |
Binding of (Rac)-JBJ-04-125-02 to EGFR is measured by surface plasmon resonance (SPR) using purified recombinant EGFR protein (wild-type and T790M/L858R mutant). The compound is flowed over the immobilized receptor, and binding affinity (KD) is calculated from the association and dissociation rates. Alternatively, a competitive binding assay using a fluorescently labeled ATP probe or a known inhibitor can be performed. No specific IC50 or KD values are reported. The selectivity is confirmed by testing against a panel of other kinases.
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| Cell Assay |
For cellular assays, NSCLC cell lines harboring EGFR T790M/L858R mutations (e.g., H1975 cells) are seeded in 96-well plates. Cells are treated with (Rac)-JBJ-04-125-02 at graded concentrations (0.1-1000 nM) for 48-72 hours. Cell viability is measured by MTT or CellTiter-Glo assays. The inhibition of EGFR phosphorylation (p-EGFR) and its downstream effectors (p-AKT, p-ERK) is assessed by Western blot. Apoptosis is measured by Annexin V/PI staining, and cell cycle distribution is analyzed by flow cytometry. Cell lines with wild-type EGFR (e.g., A431) are used as controls for selectivity.
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| Animal Protocol |
For in vivo evaluation, 6-8-week-old female BALB/c nude mice bearing subcutaneous H1975 xenografts (EGFR T790M/L858R) are used. Mice are randomized when tumors reach approximately 100-150 mm3. (Rac)-JBJ-04-125-02 is administered orally (by gavage) at doses of 10-50 mg/kg once daily for 2-4 weeks. Tumor volumes are measured twice weekly. At the study endpoint, tumors are collected for Western blot analysis of p-EGFR and downstream markers, and for immunohistochemistry (Ki-67, cleaved caspase-3). Body weight is monitored for toxicity. No specific protocols are described in the search results.
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| ADME/Pharmacokinetics |
(Rac)-JBJ-04-125-02 acetate (C2₉H3₈ClN₇O4·xC2H4O2, MW = 584.12 free base) is a solid powder. For storage, the powder should be kept at -20degC for up to 3 years, sealed and protected from light. For in vitro use, stock solutions in DMSO (e.g., 50 mg/mL, 85.6 mM) can be prepared and stored at -80degC for up to 6 months. For in vivo oral administration, it can be formulated in 10% DMSO / 40% PEG300 / 5% Tween-80 / 45% saline. No detailed PK parameters are reported.
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| Toxicity/Toxicokinetics |
No specific toxicity data for (Rac)-JBJ-04-125-02 acetate are reported. As a research-grade allosteric EGFR inhibitor, it is not intended for human or veterinary use. Standard laboratory safety precautions for handling chemicals should be followed, including the use of gloves, lab coat, and safety goggles. Off-target toxicity is expected to be lower than with ATP-competitive inhibitors due to its selectivity for the mutant receptor, but no formal toxicology studies are available.
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| References | |
| Additional Infomation |
(Rac)-JBJ-04-125-02 is a fourth-generation allosteric EGFR inhibitor developed to overcome resistance to third-generation EGFR inhibitors like osimertinib. The compound was discovered by researchers at the University of California, San Francisco (UCSF) and the University of California, Berkeley. JBJ-04-125-02 targets the same allosteric site as EAI001 and EAI045 but is structurally distinct and more potent. The “rac” designation indicates the compound is a racemic mixture of enantiomers. The compound has been studied in preclinical models of NSCLC and has shown activity against L858R/T790M/C797S triple mutants in some studies. It is for research use only.
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| Molecular Formula |
C29H26FN5O3S.1/3C2H4O2
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| Molecular Weight |
563.63
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| Appearance |
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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : 100 mg/mL (177.42 mM; with sonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.44 mM)(Saturation unknown) in 10% DMSO 40% PEG300 5% Tween-80 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, add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix well; then add 50 μL Tween-80 to the above system and mix well; then add 450 μL saline to make it 1 mL. *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7742 mL | 8.8711 mL | 17.7421 mL | |
| 5 mM | 0.3548 mL | 1.7742 mL | 3.5484 mL | |
| 10 mM | 0.1774 mL | 0.8871 mL | 1.7742 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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