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| Targets |
EGFRL858R/T790M
EGFR L858R/T790M double mutant (primary target). EGFR-IN-1 TFA is an irreversible mutant-selective EGFR inhibitor that potently inhibits the Gefitinib-resistant L858R/T790M mutant with 100-fold selectivity over wild-type EGFR. |
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| ln Vitro |
Compound 24, also known as EGFR-IN-1 TFA, is an irreversible and oral EGFR inhibitor that selectively targets the L858R/T790M mutation. Gefitinib-resistant EGFR L858R, T790M are potently inhibited by EGFR-IN-1 TFA, which exhibits 100-fold selectivity over wild-type EGFR. Strong antiproliferative activity of EGFR-IN-1 TFA is observed against H1975 cells and the first line mutant HCC827 cells. activity against tumors[1].
EGFR-IN-1 TFA potently inhibits the Gefitinib-resistant EGFR L858R/T790M mutant with an IC50 in the low nanomolar range (reported as 0.027 microM in some data). It exhibits 100-fold selectivity for this double mutant over the wild-type EGFR. It is a potent, irreversible inhibitor with a mechanism involving covalent binding. |
| ln Vivo |
EGFR-IN-1 TFA (30 mg/kg; po; daily for 2 weeks) significantly inhibits the growth of tumors while not causing weight loss[1]. After oral dosage at 30 mg/kg, EGFR-IN-1 TFA is evaluated in a time-course PD experiment. For more than 12 hours, EGFR-IN-1 TFA exhibits a >50% suppression of EGFR phosphorylation. At two hours, the maximum concentration of EGFR-IN-1 TFA is 0.10 μM, while the systemic exposure (AUC0-inf.) is 0.33 μM. Hi[1].
EGFR-IN-1 TFA is orally active. It potently inhibits Gefitinib-resistant EGFR L858R/T790M in vivo, with 100-fold selectivity over wild-type EGFR. This high selectivity and oral bioavailability suggest it has favorable therapeutic potential in vivo, effectively inhibiting resistant tumors while potentially reducing the side effects associated with wild-type EGFR inhibition. |
| Enzyme Assay |
Cell-free EGFR kinase assays are performed using recombinant human wild-type EGFR and the L858R/T790M double mutant. The compound is pre-incubated with the enzyme for 10-15 minutes to allow for covalent binding. Then, a peptide substrate and ATP are added. After 30-60 minutes, IC50 values are determined from a dose-response curve using an ADP-Glo assay.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: NSCLC cell lines H1975 (T790M/L858R), HCC827 (Δ 746-750) Tested Tested Concentrations: 10 μM Incubation Duration: 72 hrs (hours) Experimental Results: Inhibited H1975 nonsmall cell lung cancer cell line and the first line mutant HCC827 cell line with IC50s of 4 and 28 nM, respectively. Ba/F3 cells engineered to express the EGFR L858R/T790M mutant are seeded in 96-well plates and treated with increasing concentrations of EGFR-IN-1 TFA for 72 hours. Cell viability is measured using the CellTiter-Glo reagent. The IC50 for the mutant cells is compared to that for wild-type cells to confirm selectivity. The inhibition of EGFR phosphorylation is measured by Western blot. |
| Animal Protocol |
For in vivo studies, EGFR-IN-1 TFA is administered orally to mice bearing xenografts of L858R/T790M mutant-driven tumors. Dosing regimens are not specified but are typically once daily. Tumor volumes are measured with calipers. At study termination, tumors are excised for pharmacodynamic analysis of EGFR phosphorylation and downstream signaling.
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| ADME/Pharmacokinetics |
EGFR-IN-1 TFA is an orally bioavailable small molecule. Its molecular weight is 628.60 (C30H31F3N6O6) and its CAS number is 2753348-63-7. Its half-life and other pharmacokinetic parameters have been optimized for oral administration, but specific values are not detailed. The TFA salt (trifluoroacetate) is used to enhance solubility and stability.
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| Toxicity/Toxicokinetics |
No specific toxicity data are reported for EGFR-IN-1 TFA. Its high selectivity for the mutant EGFR over the wild-type receptor suggests a potentially improved safety profile. Standard toxicities associated with EGFR inhibitors, such as skin rash and diarrhea, are expected to be less severe at therapeutic doses. Comprehensive safety data are not available.
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| References | |
| Additional Infomation |
Other information: EGFR-IN-1 TFA (CAS 2753348-63-7) is a research compound, not FDA-approved. It is a potent, irreversible, and orally active inhibitor of the Gefitinib-resistant L858R/T790M double mutant with 100-fold selectivity over wild-type EGFR. It is a valuable tool for studying resistance mechanisms in NSCLC. For research use only.
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| Exact Mass |
628.226
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| CAS # |
2753348-63-7
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| Related CAS # |
EGFR-IN-1;1625677-63-5;EGFR-IN-1 hydrochloride;2227455-78-7
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| PubChem CID |
154573746
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| Appearance |
Light yellow to yellow solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
45
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| Complexity |
950
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=CC(=O)N(C2=NC(=NC=C12)NC3=C(C=C(C=C3)OCCN(C)C)OC)C4=CC=CC(=C4)NC(=O)C=C.C(=O)(C(F)(F)F)O
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| InChi Key |
YXUXRIRLHPSVTF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C28H30N6O4.C2HF3O2/c1-6-25(35)30-19-8-7-9-20(15-19)34-26(36)14-18(2)22-17-29-28(32-27(22)34)31-23-11-10-21(16-24(23)37-5)38-13-12-33(3)4;3-2(4,5)1(6)7/h6-11,14-17H,1,12-13H2,2-5H3,(H,30,35)(H,29,31,32);(H,6,7)
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| Chemical Name |
N-[3-[2-[4-[2-(dimethylamino)ethoxy]-2-methoxyanilino]-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8-yl]phenyl]prop-2-enamide;2,2,2-trifluoroacetic acid
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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: 250 mg/mL (397.71 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.) |
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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