PQR626 is a rapamycin derivative that acts as a highly potent, selective, orally active, and brain-penetrant mTOR inhibitor. It exhibits remarkable inhibitory effects on the mammalian target of the rapamycin (mTOR) pathway, with an IC50 value of 5 nM and a Ki value of 3.6 nM. This compound, PQR626, holds promise for advancing research in the field of neurological disorders.

mTOR:5 nM (IC50)

PQR626, administered at concentrations ranging from 0.04 to 5 μM for a duration of one hour, demonstrates inhibitory capability with IC50 values of 197 nM and 87 nM for the phosphorylation of PKB S473 and S6 S235/S236, respectively, as assessed by in-cell western blot. This compound effectively targets mTOR signaling pathway components, including S6 kinase (S6K), S6 ribosomal protein (S6rP), and 4E-binding protein (4E-BP), as corroborated by Western Blot Analysis using A2058 cells treated with varied concentrations (0.04 μM to 5 μM) over one hour, showing inhibition of mTOR activity within cells[1].

PQR626, administered orally at dosages ranging from 10 to 50 mg/kg twice daily for 90 days, significantly mitigates the mortality induced by Tsc1 loss in BALB/c nude female mice and Tsc1 GFAP CKO mouse models, as opposed to the control vehicle[2]. Additionally, pharmacokinetic analysis in female C57BL/6J mice receiving a 10 mg/kg daily dose for 4 days reveals a terminal elimination half-life of 3.0 hours, attributed to high plasma clearance (1096 ng/mL), indicating efficient systemic elimination[2]. These results highlight PQR626’s potential therapeutic efficacy and its pharmacokinetic profile, underscoring its capacity to reduce Tsc1-induced mortality with favorable clearance rates.