Target nature :
FLT3
CAS n° :
823837-22-5
Mecanism of action :
negative allosteric inhibitor (Ki: 6.6 microM)
Physico-chemical properties :
MW: 394.87
logP: 3.27
Probe availability :
The probe is available at the LIT (Dr. Didier ROGNAN, email: rognan@unistra.fr)
Princeps reference :
Rivat C, Sar C, Mechaly I, Leyris JP, Diouloufet L, Sonrier C, Philipson Y, Lucas O, Mallié S, Jouvenel A, Tassou A, Haton H, Venteo S, Pin JP, Trinquet E, Charrier-Savournin F, Mezghrani A, Joly W, Mion J, Schmitt M, Pattyn A, Marmigère F, Sokoloff P, Carroll P, Rognan D, Valmier J. (2018) Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice. Nat Commun. 9:1042.
More bibliography :
Other available information on the probe :
- chemically stable, stable in mouse plasma over 24h - aqueous solubility: 12 microg/mL- microsomal stability (human liver microsomes): 20 min- Caco-2 permeation A-B: 22.3 10-6 cm/s; B-A: 3.2 10-6 cm/s- log [brain]/[plasma]: -1.0 after 20 minfunctional antagonist) - CYP inhibition (10 microM): 1A2 (63%), 2B6 (36%), 2C8 (85%), 2C9 (84%), 2C19 (64%), 2D6 (60%), 3AR '25%)
Other information on the target :
FLT3 is a receptor tyrosine kinase whose is responsible of triggering and maintaining peripheral neuropathic pain afte rnerve lesion.
Selectivity profile :
- selective over 45 kinases and 25 receptor tyrosine kinases - Off-targets: CB1 receptor (EC50=3.2 microM; functional agonist), 5-HT2B (IC50= 2.0 microM; functional antagonist)
In vivo data :
anti-hyparalgesic and anti-allodynic in all rodent models of neuropathic pain (CCI, SNL, oxaliplatine) at doses ranging from 2-5 mg/kg (p.o., i.p., s.c.)
In vitro data :
IC50 (HEK-293 cells): 12 microM IC50 (neuronal FLT3, DRG neurons): 150 nM
Toxicity :
-no apparent toxicity in rodents - no cytotoxicity (10 microM, 72h) on MCF-7, HepG2 and HEK293 cell lines.- negative in the genotoxic AMES test
Chaine SMILES :
O=C(Nc1cc(Cl)ccc1O)c3cccc(S(=O)(=O)N2CCCCC2)c3
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