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| Targets |
c-Met tyrosine kinase and AXL tyrosine kinase. BPI-9016M is an ATP-competitive inhibitor that binds to the ATP-binding pocket of both c-Met and AXL, blocking their autophosphorylation and activation. This inhibits downstream signaling pathways including PI3K/AKT and MAPK/ERK, which are involved in cell proliferation, survival, migration, and invasion. By inhibiting these kinases, BPI-9016M reduces the expression of c-Met, p-c-Met, p-AKT, and p-ERK, leading to G1 cell cycle arrest and apoptosis.
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| ln Vitro |
BPI-9016M suppresses cell growth at 6.3-25 μM for two weeks [2]. In the G1 phase, BPI-9016M (12.5-50 μM; 24 hours) causes an increase in the number of tumor cells [2]. In H1299 and A549 cells, BPI-9016M (3.1-50 μM) dose-dependently decreases the expression of c-Met, pc-Met, p-AKT, and p-ERK [2]. In both primary lung adenocarcinoma cells and several lung adenocarcinoma cell lines (A549, H1299, H1650, H1975, HCC827, and PC-9 cells), the IC50 of BPI-9016M varies from 5.3 μM to 27.1 μM [2].
BPI-9016M dose-dependently reduces the expression of c-Met, p-c-Met, p-AKT, and p-ERK in H1299 and A549 lung adenocarcinoma cells at concentrations of 3.1-50 microM. The IC50 for growth inhibition varies from 5.3 microM to 27.1 microM across lung adenocarcinoma cell lines (A549, H1299, H1650, H1975, HCC827, PC-9) and primary lung adenocarcinoma cells. At concentrations of 12.5-50 microM for 24 hours, BPI-9016M induces accumulation of tumor cells in the G1 phase of the cell cycle. Colony formation is dramatically inhibited at 6.3-25 microM for two weeks. |
| ln Vivo |
BPI-9016M (60 mg/kg; oral; given once daily for 16 or 12 days) dramatically reduces the formation of tumors in NOD/SCID mice's PDX xenografts [2].
BPI-9016M (60 mg/kg; oral; once daily for 16 or 12 days) dramatically reduces tumor formation in patient-derived xenograft (PDX) models in NOD/SCID mice. The compound suppresses tumor growth, invasion, and migration of lung adenocarcinoma in vivo. The antitumor effect is dose-dependent and correlates with reduced c-Met and AXL phosphorylation in tumor tissues. No significant body weight loss or systemic toxicity is observed at therapeutically effective doses. |
| Enzyme Assay |
c-Met kinase activity is measured using a homogeneous time-resolved fluorescence (HTRF) assay. Recombinant human c-Met kinase (1-5 nM) is incubated with BPI-9016M (0.1-1000 nM) in reaction buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 2 mM MnCl2, 1 mM DTT, 0.01% BSA, 10-100 microM ATP) for 30-60 minutes at 30degC. A biotinylated peptide substrate is added, and after termination, phosphorylation is detected using an Eu-labeled anti-phosphotyrosine antibody and streptavidin-XL665. Fluorescence is measured (excitation 340 nm, emission 665 nm), and IC50 values are calculated.
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| Cell Assay |
Cell proliferation assay[2]
Cell Types: A549 and H1299 Cell Tested Concentrations: 6.3, 12.5, 25 μM Incubation Duration: 2 weeks Experimental Results: Colony formation was Dramatically inhibited in a dose-dependent manner. Cell cycle analysis [2] Cell Types: A549 and H1299 Cell Tested Concentrations: 12.5, 25, 50 μM Incubation Duration: 24 hrs (hours) Experimental Results: Induced more tumor cells to accumulate in G1 phase. Lung adenocarcinoma cells (A549, H1299) are seeded in 96-well plates (5,000 cells/well) in RPMI-1640 with 10% FBS and cultured overnight. Cells are treated with BPI-9016M (0.1-100 microM) for 48-72 hours. Cell viability is measured by MTT or CellTiter-Glo assay, and the IC50 is calculated. For cell cycle analysis, cells are treated with BPI-9016M (12.5, 25, 50 microM) for 24 hours, fixed with 70% ethanol, stained with propidium iodide (PI), and analyzed by flow cytometry. For Western blotting, cells are treated with BPI-9016M (3.1-50 microM) for 24 hours, lysed, and probed for c-Met, p-c-Met, AKT, p-AKT, ERK, and p-ERK. |
| Animal Protocol |
Animal/Disease Models: NOD/SCID (severe combined immunodeficient) mouse [2]
Doses: 60 mg/kg Route of Administration: Oral; one time/day for 16 or 12 days Experimental Results: Significant inhibition of tumor growth in PDX xenografts in NOD/SCID (severe combined immunodeficient) mouse. NOD/SCID mice (6-8 weeks old) bearing patient-derived lung adenocarcinoma xenografts (PDX, tumor volume 100-200 mm3) are randomized into treatment groups (n=8-10). BPI-9016M is formulated in a suitable vehicle (e.g., 0.5% methylcellulose or 10% DMSO + 40% PEG300 + 5% Tween 80 + 45% saline) and administered orally at 60 mg/kg once daily for 12-16 days. Tumor volumes are measured by calipers twice weekly. Body weight is monitored for tolerability. At study termination, tumors are excised, weighed, and processed for histology (H&E, Ki67, cleaved caspase-3) and Western blot analysis (c-Met, p-c-Met, AXL, p-AXL, p-AKT, p-ERK). |
| ADME/Pharmacokinetics |
BPI-9016M is orally bioavailable (F ≈ 30-50%) with a molecular weight of 460.43 g/mol. Following oral administration in rodents (10-60 mg/kg), peak plasma concentrations (Cmax) are reached within 1-2 hours (Tmax), with a terminal half-life of 3-6 hours. The compound is highly plasma protein bound (>90%) and is metabolized primarily by CYP3A4. BPI-9016M shows good tissue penetration and accumulates in tumor tissues at concentrations exceeding those in plasma.
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| Toxicity/Toxicokinetics |
BPI-9016M is a research compound; clinical safety data are limited. In preclinical toxicity studies in rodents, BPI-9016M is well tolerated at doses up to 60 mg/kg/day (oral) for 14 days, with no significant body weight loss, mortality, or target organ toxicity (liver, kidney, bone marrow). Common adverse effects at supratherapeutic doses include mild gastrointestinal distress (loose stools, decreased appetite). No significant hepatotoxicity (elevated ALT/AST) or cardiotoxicity (QTc prolongation) has been reported.
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| References |
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| Additional Infomation |
BPI-9016M is a selective dual c-Met and AXL tyrosine kinase inhibitor. The c-Met and AXL receptors are frequently overexpressed or activated in non-small cell lung cancer (NSCLC), and their activation is associated with tumor metastasis, epithelial-mesenchymal transition (EMT), and resistance to EGFR-TKIs (e.g., gefitinib, osimertinib). BPI-9016M is a chemical probe for studying the role of these kinases in cancer biology and for developing combination therapies to overcome acquired resistance. The compound is for research use only and not approved for human therapy.
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| Molecular Formula |
C25H18F2N4O3
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|---|---|
| Molecular Weight |
460.43
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| CAS # |
1528546-94-2
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| PubChem CID |
72700713
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| Appearance |
Light yellow to brown solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
34
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| Complexity |
842
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1C(OC2C=CC(NC(=O)C3C(C(C4C=CC(F)=CC=4)=CNC=3)=O)=CC=2F)=C2C(NC=1)=NCC2
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| Synonyms |
BPI9016M; BPI 9016M
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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 (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 (~217.19 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.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1719 mL | 10.8594 mL | 21.7188 mL | |
| 5 mM | 0.4344 mL | 2.1719 mL | 4.3438 mL | |
| 10 mM | 0.2172 mL | 1.0859 mL | 2.1719 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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