Home Protein Tyrosine Kinase c-Met inhibitor SAR125844

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SAR125844 c-Met inhibitor

Cat.No.S7564

SAR125844 is a potent intravenously active and highly selective Met (c-Met) kinase inhibitor, displaying nanomolar activity against the wild-type kinase (IC50 value of 4.2 nmol/L) and H1094Y, Y1235D, M1250T, L1195V, and D1228H kinase domain mutants (IC50 values of 0.22, 1.7, 6.5, 65, and 81 nmol/L, respectively).
SAR125844 c-Met inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 550.63

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Quality Control

Batch: S756401 DMSO]11 mg/mL]false]Water]˂1 mg/mL]false]Ethanol]˂1 mg/mL]false Purity: 99.02%
99.02

Solubility

In vitro
Batch:

DMSO : 11 mg/mL (19.97 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : ˂1 mg/mL

Ethanol : ˂1 mg/mL

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In vivo
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Chemical Information, Storage & Stability

Molecular Weight 550.63 Formula

C25H23FN8O2S2

 Storage (From the date of receipt) 3 years -20°C powder
CAS No. 1116743-46-4 -- Storage of Stock Solutions

Synonyms N/A Smiles C1COCCN1CCNC(=O)NC2=NC3=C(S2)C=C(C=C3)SC4=NN=C5N4N=C(C=C5)C6=CC=C(C=C6)F

Mechanism of Action

Targets/IC50/Ki
MET H1094Y
(Cell-free assay)
0.22 nM
MET Y1235D
(Cell-free assay)
1.7 nM
WT MET
(Cell-free assay)
4.2 nM
MET M1250T
(Cell-free assay)
6.5 nM
TRKA/NTRK1
(Cell-free assay)
39 nM
PDGFRα-V561D
(Cell-free assay)
55 nM
MET L1195V
(Cell-free assay)
65 nM
MET D1228H
(Cell-free assay)
81 nM
AXL
(Cell-free assay)
87 nM
MER
(Cell-free assay)
105 nM
MET Y1230H
(Cell-free assay)
204 nM
In vitro

SAR125844 is an ATP-competitive and reversible inhibitor. The biochemical selectivity of this compound is documented in a panel of 275 human kinases and against tubulin. It is moderately active on RON, a close structural homolog of MET, with IC50 value of approximately 740 nmol/L, suggesting that this inhibitor is highly (>100-fold) selective for the MET kinase over RON. Minimal inhibitory activity is identified on 5 additional kinases with IC50 values below 300 nmol/L, including TRKA/NTRK1 (39 nmol/L), TRKB/NTRK2 (280 nmol/L), PDGFRα-V561D (55 nmol/L), AXL (87 nmol/L), and MER (105 nmol/L). Biochemical activities on Aurora A and Aurora B are detected with IC50 values of 320 and 820 nmol/L, respectively, but these activities do not translate into cellular activity as demonstrated by the lack of antiproliferative activity in tumor cell lines without MET gene amplification. No activity on tubulin is detected up to 25 μmol/L of this chemical. It inhibits MET autophosphorylation in cell-based assays in the nanomolar range, and promotes low nanomolar proapoptotic and antiproliferative activities selectively in cell lines with MET gene amplification or pathway addiction.
In vivo

In PK studies in mice, the oral bioavailability of SAR125844 is low (∼2%), in line with its moderate Caco-2 permeability. In female SCID mice bearing xenograft tumors based on the MET-amplified Hs 746T human gastric tumor cell line, a single intravenous administration at 20 mg/kg is performed. plasma exposure of this compound (area under the curve (AUC)) is 6190 h·ng/mL, the clearance moderate (CL = 3.1 L/h/kg), and the volume of distribution is large (Vss = 4.2 L/kg). A rapid and sustained uptake of this chemical in tumor tissue is observed, associated with a slower decrease of concentration from tumor tissue compared to the plasma concentration. The clearances of this agent in mice, rats, and dogs are moderate. The plasma terminal elimination half-life (t1/2) is moderate (rats and dogs) to long (mice). The volume of distribution at steady state is moderate in dogs and large in rodents. In two MET-amplified human gastric tumor xenograft models, SNU-5 and Hs 746T, intravenous treatment with this compound leads to potent, dose- and time-dependent inhibition of the MET kinase and to significant impact on downstream PI3K/AKT and RAS/MAPK pathways. Daily or every-2-days intravenous treatment of this chemical promots a dose-dependent tumor regression in MET-amplified human gastric cancer models at tolerated doses without treatment-related body weight loss.
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02435121 Completed
Neoplasm Malignant
Sanofi
 November 2015 Phase 2
NCT01657214 Completed
Neoplasm Malignant
Sanofi
 September 2012 Phase 1
NCT01391533 Completed
Malignant Solid Tumors
Sanofi
 July 2011 Phase 1

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