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Purity: ≥98%
SAR125844 is a novel, potent, highly selective, reversible and ATP-competitive inhibitor of MET receptor tyrosine kinase (RTK) for intravenous administration, with an IC50 of 4.2 nM. In tests using cells, it demonstrates inhibition of MET autophosphorylation. Against the M1250T and Y1235D mutants as well as the wild-type kinase (IC50 value of 4.2 nmol/L), SAR125844 demonstrated nanomolar activity. SAR125844 was found to be very selective for MET kinase based on extensive biochemical profiling. SAR125844 selectively promotes low nanomolar proapoptotic and antiproliferative activities in cell lines with MET gene amplification or pathway addiction, and it inhibits MET autophosphorylation in cell-based assays in the nanomolar range. Intravenous administration of SAR125844 results in a strong, dose- and time-dependent inhibition of MET kinase and a notable effect on downstream PI3K/AKT and RAS/MAPK pathways in two MET-amplified human gastric tumor xenograft models, SNU-5 and Hs 746T. SAR125844 nanosuspension formulation produced MET kinase inhibition for up to 7 days. When administered intravenously on a daily or every two-day basis, SAR125844 caused a dose-dependent tumor regression at tolerated doses in MET-amplified human gastric cancer models, without causing weight loss associated with treatment. SAR125844's clinical development in patients with MET-amplified and MET pathway-addicted tumors is supported by our data, which showed that it is a potent and selective MET kinase inhibitor with a favorable preclinical toxicity profile.
| Targets |
MET H1094Y (IC50 = 0.22 nM); MET Y1235D (IC50 = 1.7 nM); WT MET (IC50 = 4.2 nM); MET M1250T (IC50 = 6.5 nM); TRKA/NTRK1 (IC50 = 39 nM)
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| ln Vitro |
SAR125844 is a reversible, ATP-competitive inhibitor. SAR125844's biochemical selectivity has been demonstrated against tubulin and a panel of 275 human kinases. With an IC50 value of roughly 740 nmol/L, SAR125844 exhibits moderate activity on RON, a close structural homolog of MET. This suggests that SAR125844 is highly (>100-fold) selective for the MET kinase over RON. Five other kinases (TRKA/NTRK1 (39 nmol/L), TRKB/NTRK2 (280 nmol/L), PDGFRα-V561D (55 nmol/L), AXL (87 nmol/L), and MER (105 nmol/L)) have minimal inhibitory activity identified on them. With IC50 values of 320 and 820 nmol/L, respectively, biochemical activities on Aurora A and Aurora B are found; however, as shown by the absence of antiproliferative activity in tumor cell lines lacking MET gene amplification, these activities do not translate into cellular activity. Up to 25 μmol/L of SAR125844, no tubulin activity is found. SAR125844 preferentially stimulates low nanomolar proapoptotic and antiproliferative activities in cell lines with MET gene amplification or pathway addiction, and it inhibits MET autophosphorylation in cell-based assays in the nanomolar range[2].
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| ln Vivo |
SAR125844 has a moderate Caco-2 permeability, which is consistent with its low oral bioavailability of about 2% in mouse PK studies. The MET-amplified Hs 746T human gastric tumor cell line is used to create xenograft tumors in female SCID mice. An intravenous dose of 20 mg/kg is administered once. The area under the curve (AUC) for SAR125844's plasma exposure is 6190 h·ng/mL, its clearance is moderate (CL = 3.1 L/h/kg), and its volume of distribution is large (Vss = 4.2 L/kg). Tumor tissue rapidly and continuously absorbs SAR125844; this is accompanied by a slower decline in tumor tissue concentration relative to plasma concentration. SAR125844 has moderate clearances in mice, rats, and dogs. In rats and dogs, the plasma terminal elimination half-life (t1/2) ranges from moderate to long (mice). In dogs, the volume of distribution at steady state is moderate, but in rodents, it is large[1]. Intravenous treatment with SAR125844 results in potent, dose- and time-dependent inhibition of the MET kinase and has a significant effect on downstream PI3K/AKT and RAS/MAPK pathways in two MET-amplified human gastric tumor xenograft models, SNU-5 and Hs 746T. Intravenous SAR125844 treatment given once a day or every two days induces a dose-dependent tumor regression in MET-amplified human gastric cancer models at doses tolerable for the patient without causing treatment-related weight loss[2].
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| Cell Assay |
Complete medium is used to seed MKN-45, Hs 746T, and SNU-5 cells in poly d-lysine 96-well plates. After one hour of incubation at escalating SAR125844 concentrations on plates, cell lysates are produced.
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| Animal Protocol |
8-10 weeks old SCID female mice
20 mg/kg i.v. |
| References |
| Molecular Formula |
C25H23N8O2FS2
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|---|---|
| Molecular Weight |
550.63092
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| Exact Mass |
550.14
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| Elemental Analysis |
C, 54.53; H, 4.21; F, 3.45; N, 20.35; O, 5.81; S, 11.64
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| CAS # |
1116743-46-4
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| Related CAS # |
1116743-46-4
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| Appearance |
Solid powder
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| SMILES |
C1COCCN1CCNC(=O)NC2=NC3=C(S2)C=C(C=C3)SC4=NN=C5N4N=C(C=C5)C6=CC=C(C=C6)F
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| InChi Key |
ODIUNTQOXRXOIV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H23FN8O2S2/c26-17-3-1-16(2-4-17)19-7-8-22-30-31-25(34(22)32-19)37-18-5-6-20-21(15-18)38-24(28-20)29-23(35)27-9-10-33-11-13-36-14-12-33/h1-8,15H,9-14H2,(H2,27,28,29,35)
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| Chemical Name |
1-[6-[[6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl]-1,3-benzothiazol-2-yl]-3-(2-morpholin-4-ylethyl)urea
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| Synonyms |
SAR-125844; SAR 125844; SAR125844
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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: ~11 mg/mL (~20 mM)
Ethanol: ˂1 mg/mL Water: ˂1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.25 mg/mL (4.09 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 22.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8161 mL | 9.0805 mL | 18.1610 mL | |
| 5 mM | 0.3632 mL | 1.8161 mL | 3.6322 mL | |
| 10 mM | 0.1816 mL | 0.9081 mL | 1.8161 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01657214 | Completed | Drug: SAR125844 | Neoplasm Malignant | Sanofi | September 2012 | Phase 1 |
| NCT02435121 | Completed | Drug: SAR125844 | Neoplasm Malignant | Sanofi | November 2015 | Phase 2 |
| NCT01391533 | Completed | Drug: SAR125844 | Malignant Solid Tumors | Sanofi | July 2011 | Phase 1 |
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