Tolebrutinib, also known as SAR442168, is a potent, selective, orally active and brain-penetrating BTK inhibitor with IC50 values of 0.4 nM and 0.7 nM in Ramos B cells and HMC microglia cells, respectively.Tolebrutinib has shown efficacy against CNS immunity. Tolebrutinib is used in multiple sclerosis (MS) studies[1][2].Tolebrutinib blocks BCR-mediated immune cell activation (IC50=10 nM) and Fc receptor activation (IC50 of 166 and 9.6 nM for FcεR and FcγR, respectively)[2].PRN2246 inhibits microglia FcγR activation through persistent BTK occupancy with an IC50 value of 157 nM[2].
Tolebrutinib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Primary mouse microglia
100 nM
15 minutes
To evaluate the effect of tolebrutinib on BTK phosphorylation after IgG stimulation, results showed that tolebrutinib blocked the increase in BTK phosphorylation.
Nat Commun. 2024 Nov 22;15(1):10116
BV-2 mouse microglial cell line
0.005-200 nM
30 minutes
To evaluate the effect of PRN2675 on BTK autophosphorylation, results showed that PRN2675 rapidly reduced levels of phosphorylated BTK (Tyr223).
Nat Commun. 2024 Nov 22;15(1):10116
Human induced pluripotent stem cell (hiPSC)-derived microglia
100 nM
6 hours
To evaluate the effect of tolebrutinib on the transcriptional response after FcγR stimulation, results showed that tolebrutinib significantly altered the microglial transcriptome.
Nat Commun. 2024 Nov 22;15(1):10116
Tolebrutinib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Experimental autoimmune encephalomyelitis (EAE) model
Oral
15 mg/kg
Once daily for 10 days
To evaluate the effect of PRN2675 on disease manifestations in the EAE model, results showed that PRN2675 significantly reduced clinical disease scores and plasma neurofilament heavy chain (NfH) levels.
Nat Commun. 2024 Nov 22;15(1):10116
Tolebrutinib 动物研究
Animal study
In a myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) model, Tolebrutinib produces dose-dependent protection when administered orally, q.d., for 28 days at a dose range of 1-5 mg/kg[2].
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