| Size | Price | Stock | Qty |
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| 50mg |
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| 500mg | |||
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BMS-817378 is a novel and potent MET inhibitor
| Targets |
c-MET (mesenchymal-epithelial transition factor) receptor tyrosine kinase - inhibitor [1]
- Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) - inhibitor [1] |
|---|---|
| ln Vivo |
This Phase I trial enrolled 18 patients with advanced refractory solid tumors (primarily digestive tract cancers, including 9 with hepatocellular carcinoma). Patients received Metatinib in a 3+3 dose-escalation design (25, 50, 100, 200, 300 mg/day). [1]
- The maximum tolerated dose (MTD) was determined to be 200 mg/day. Dose-limiting toxicities (DLTs) observed were hand-foot skin reaction, diarrhea, and liver dysfunction. [1] - The most common treatment-related adverse events (TRAEs) of any grade were skin toxicity (palmar-plantar erythrodysesthesia syndrome, 50%), diarrhea (33.3%), and liver dysfunction (27.8%). [1] - Grade 3 TRAEs were observed in the 200 mg and 300 mg cohorts, including skin toxicity, diarrhea, and liver dysfunction. No grade 4 or 5 TRAEs were reported. [1] - The objective response rate (ORR) was 11.1% (2 out of 18 patients achieved partial response, PR). One patient in the 200 mg cohort with rectal cancer and MET IHC 2+/exon 14 skipping achieved a PR with 8.5 months PFS. Another patient in the 300 mg cohort with esophageal cancer achieved a PR with 3 months PFS. [1] - The disease control rate (DCR) was 61.1% (11 out of 18 patients, including 2 PR and 9 stable disease, SD). The median progression-free survival (PFS) for all patients was 2.75 months (range 1.0-8.5 months). For the 10 patients in the extended treatment period, median PFS was 4.0 months. [1] - Tumor burden shrinkage was observed in 4 patients. [1] - MET immunohistochemistry (IHC) and FISH analysis were performed on tumor samples. Two patients had IHC 2+, three had IHC 1+, and thirteen were IHC 0. No MET gene amplification was detected. One patient with IHC 2+ and MET exon 14 skipping had a PR and the longest PFS of 8.5 months. Another patient with IHC 2+ had a PFS of 5.5 months, suggesting a possible association between MET status and efficacy. [1] |
| ADME/Pharmacokinetics |
After single-dose oral administration, Metatinib is rapidly absorbed and metabolized to form a reactive metabolite, SCR-1510. [1]
- The mean time to achieve maximum concentration (Tmax) for SCR-1510 was approximately 2.0-3.0 hours. [1] - The terminal elimination half-life (t1/2) for SCR-1510 ranged from 8 to 14 hours. [1] - Following multiple-dose administration, continuous accumulation of SCR-1510 was observed. The concentration at day 29 was more than twice that at day 1. [1] - PK parameters including Cmax, Tmax, AUC0-t, AUC0-∞, and fluctuation coefficient were calculated using a noncompartmental analysis model. [1] - Blood samples for PK analysis were collected pre-dose and at multiple time points (0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours) after the first dose, and pre-dose on days 8, 15, 29 and post-last-dose on day 29. [1] |
| Toxicity/Toxicokinetics |
The dose-limiting toxicities (DLTs) were hand-foot skin reaction, diarrhea, and liver dysfunction. [1]
- The most common treatment-related adverse events (TRAEs) included: - Skin toxicity (palmar-plantar erythrodysesthesia syndrome): 50% all grades, 5.6% grade 3. [1] - Diarrhea: 33.3% all grades, 5.6% grade 3. [1] - Liver dysfunction (AST/ALT elevation, blood bilirubin increase): 27.8% all grades, 5.6% grade 3. [1] - Grade 3 TRAEs were observed in one patient in the 200 mg/day cohort (skin toxicity) and two patients in the 300 mg/day cohort (severe liver dysfunction and combined liver/skin toxicity). [1] - No grade 4 or 5 TRAEs were reported. [1] - Discontinuation of study treatment due to AEs occurred in 22.2% of all patients, and in 100% of patients in the 300 mg/day cohort. [1] - The toxicity profile was similar to other VEGFR-targeting TKIs like cabozantinib, apatinib, sunitinib, anlotinib, and regorafenib, but with a lower incidence of hypertension, proteinuria, and fatigue. [1] - Skin toxicity was manageable with drug discontinuation and dose reduction. The accumulation of the metabolite SCR-1510 was suggested to correlate with observed toxicity. [1] |
| References |
| Molecular Formula |
578.85
|
|---|---|
| Molecular Weight |
578.845892429352
|
| Exact Mass |
578.056
|
| CAS # |
1174161-69-3
|
| PubChem CID |
44137813
|
| Appearance |
White to off-white solid powder
|
| Density |
1.6±0.1 g/cm3
|
| Index of Refraction |
1.687
|
| LogP |
3.58
|
| Hydrogen Bond Donor Count |
4
|
| Hydrogen Bond Acceptor Count |
12
|
| Rotatable Bond Count |
8
|
| Heavy Atom Count |
39
|
| Complexity |
1020
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
O=P(O)(OCN(C=C1C(NC2=CC=C(OC3=C(Cl)C(N)=NC=C3)C(F)=C2)=O)C=C(C4=CC=C(F)C=C4)C1=O)O
|
| InChi Key |
KXDZWUPUSDCGDD-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C24H18ClF2N4O7P/c25-21-20(7-8-29-23(21)28)38-19-6-5-15(9-18(19)27)30-24(33)17-11-31(12-37-39(34,35)36)10-16(22(17)32)13-1-3-14(26)4-2-13/h1-11H,12H2,(H2,28,29)(H,30,33)(H2,34,35,36)
|
| Chemical Name |
[3-[[4-(2-amino-3-chloropyridin-4-yl)oxy-3-fluorophenyl]carbamoyl]-5-(4-fluorophenyl)-4-oxopyridin-1-yl]methyl dihydrogen phosphate
|
| Synonyms |
BMS-817378 BMS817378 BMS 817378 SCR-1481B1 SCR 1481B1 SCR1481B1
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
|
|---|---|
| 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 | 1.7276 mL | 8.6378 mL | 17.2756 mL | |
| 5 mM | 0.3455 mL | 1.7276 mL | 3.4551 mL | |
| 10 mM | 0.1728 mL | 0.8638 mL | 1.7276 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.
Link: https://clinicaltrials.gov/ct2/show/NCT00792558
Conditions:Advanced Solid TumorsProducts are for research use only; We do not sell to patients
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