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| Targets |
BI-4020 targets the epidermal growth factor receptor (EGFR) tyrosine kinase. It is a non-covalent, macrocyclic TKI that inhibits not only the triple mutant EGFR del19 T790M C797S variant but also the double mutant EGFR del19 T790M and the primary mutant EGFR del19, while sparing activity against wild-type EGFR (EGFRwt). This selectivity profile is designed to overcome resistance mutations, particularly the C797S mutation, which renders earlier generations of TKIs ineffective.
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| ln Vitro |
BI-4020 has an IC50 of 0.6 nM for inhibiting p-EGFR del19 T790M C797S[1].
In vitro, BI-4020 is a potent inhibitor of EGFR mutants. It inhibits the triple mutant EGFR del19 T790M C797S variant with an IC50 of 0.2 nM in BaF2 cell lines and the double mutant EGFR del19 T790M and primary mutant EGFR del19 with an IC50 of 1 nM. Its non-covalent binding mechanism and macrocyclic structure contribute to its potency and selectivity. |
| ln Vivo |
BI-4020 promotes tumor regression in a mouse xenograft model of human PC-9 (EGFR del19 T790M C797S) triple mutant NSCLC [1].
In vivo, BI-4020 is an orally active compound suitable for convenient administration in animal studies. Its ability to inhibit the triple mutant EGFR del19 T790M C797S variant makes it a promising candidate for treating NSCLC patients who have developed resistance to third-generation EGFR TKIs. Specific in vivo efficacy data, including dosing regimens and animal models, would be detailed in the primary literature. |
| Enzyme Assay |
The inhibitory activity of BI-4020 is assessed using in vitro kinase assays. Recombinant EGFR kinases (wild-type and mutants) are incubated with a peptide substrate and varying concentrations of the compound in the presence of ATP. The IC50 values are calculated from dose-response curves. Its selectivity for mutant EGFR over wild-type EGFR is confirmed by comparing the IC50 values.
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| Cell Assay |
The cellular activity of BI-4020 is evaluated in BaF3 cells engineered to express different EGFR mutants. Cells are treated with varying concentrations of the compound, and cell viability is assessed using standard assays like CellTiter-Glo. The IC50 for inhibition of cell proliferation is calculated. The compound's ability to inhibit EGFR phosphorylation and downstream signaling is confirmed by Western blot.
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| Animal Protocol |
In animal studies, BI-4020 is typically administered orally to mice bearing subcutaneous xenografts of EGFR mutant tumors. Dosing regimens are determined based on its pharmacokinetic properties. Tumor growth inhibition is measured, and at study termination, tumors are harvested for pharmacodynamic analysis, including assessment of EGFR phosphorylation and apoptosis markers.
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| ADME/Pharmacokinetics |
BI-4020 is a small molecule with a molecular weight of 542.68 g/mol and a chemical formula of C30H38N8O2. It is orally active, indicating favorable bioavailability for in vivo studies. It has a purity of 98%. Detailed pharmacokinetic parameters, such as half-life and bioavailability, are available from preclinical studies.
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| Toxicity/Toxicokinetics |
Formal toxicology data for BI-4020 is not extensively documented in the provided sources, as it is a research compound. Its safety profile has not been established in comprehensive toxicology studies. However, its use in preclinical models at efficacious doses suggests it is tolerated in those contexts. Its use is limited to research applications.
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| References | |
| Additional Infomation |
(20R)-10,15,20-trimethyl-2-[(4-methylpiperazin-1-yl)methyl]-18,19,20,21-tetrahydro-15H,17H-12,8-(metheno)pyrazolo[3',4':2,3][1,5,10,12]oxatriazacycloheptadecino[12,11-a]benzimidazol-7(6H)-one is a macrocyclic compound with the molecular formula C30H38N8O2. It is a potent inhibitor of the EGFR del19 triple mutant T790M C797S and has shown efficacy in in vivo tumor xenograft regression. It has antitumor activity and is also an epidermal growth factor receptor antagonist. BI-4020 belongs to the indole, pyridinecarboxamide, ether, pyrazole, N-methylpiperazine, and macrocyclic compounds.
BI-4020 (CAS: 2664214-60-0) is a fourth-generation EGFR tyrosine kinase inhibitor designed to overcome the C797S resistance mutation. Its potent activity against the triple mutant EGFR del19 T790M C797S (IC50 = 0.2 nM) and its selectivity over wild-type EGFR make it a promising candidate for the treatment of NSCLC patients with acquired resistance to osimertinib. Its non-covalent, macrocyclic structure distinguishes it from earlier generations of EGFR TKIs. |
| Molecular Formula |
C30H38N8O2
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|---|---|
| Molecular Weight |
542.68
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| Exact Mass |
542.311
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| CAS # |
2664214-60-0
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| PubChem CID |
139600318
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.1
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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 |
2
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| Heavy Atom Count |
40
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| Complexity |
856
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CN1N=CC2C3N=C(C)C=C(C(=O)N=C4NC5=C(C=C(C=C5)CN5CCN(C)CC5)N4C[C@@H](CCCOC1=2)C)C=3 |c:13|
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| InChi Key |
AIQBYZOTCIQTGW-HXUWFJFHSA-N
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| InChi Code |
InChI=1S/C30H38N8O2/c1-20-6-5-13-40-29-24(17-31-36(29)4)26-16-23(14-21(2)32-26)28(39)34-30-33-25-8-7-22(15-27(25)38(30)18-20)19-37-11-9-35(3)10-12-37/h7-8,14-17,20H,5-6,9-13,18-19H2,1-4H3,(H,33,34,39)/t20-/m1/s1
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| Chemical Name |
(11R)-5,11,26-trimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7-oxa-4,5,13,20,22,27-hexazapentacyclo[22.3.1.02,6.013,21.014,19]octacosa-1(27),2(6),3,14(19),15,17,20,24(28),25-nonaen-23-one
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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 (~460.68 mM)
1M HCl : 100 mg/mL (~184.27 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.83 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 (3.83 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 (3.83 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 | 1.8427 mL | 9.2135 mL | 18.4271 mL | |
| 5 mM | 0.3685 mL | 1.8427 mL | 3.6854 mL | |
| 10 mM | 0.1843 mL | 0.9214 mL | 1.8427 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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