CZ415

CZ415 is a potent and highly selective mTOR inhibitor with a pIC₅₀ of 8.07. CZ415 inhibits mTORC1 and mTORC2 protein complex. IC50 & Target: pIC50: 8.07 (mTOR)^[1]
IC50: 14.5 nM (pS6RP, in cellular assays), 14.8 nM (pAKT, in cellular assays), 226 nM (IFNγ, in whole blood assays)^[1] In Vitro: Inhibition of phosphorylation for both downstream targets results in 14.5 nM IC₅₀ for pS6RP and 14.8 nM for pAKT. The immunosuppressive effect of CZ415 is measured by detecting secreted IFNγ after 18 hours in stimulated human whole blood and the resulting IC₅₀ is 226 nM. As a predictor for cardiotoxicity, the activity of CZ415 against the human cardiac ion channel hERG is assessed in a whole-cell patch-clamp assay in HEK293 cells resulting in an IC₅₀ of 48 μM^[1]. In Vivo: CZ415 is a highly selective mTOR inhibitor showing in vivo efficacy in a collagen induced arthritis (CIA) model. For full characterization of CZ415 and to enable improved dose predictions, the pharmacokinetic (PK) profile is assessed in rat. PK and oral bioavailability are determined after of 1 mg/kg intravenous (iv) bolus and 3 mg/kg oral (po) administration. The observed plasma clearance, corresponding to 45% liver blood flow, suggests that sufficient levels of free compound are circulating in the animal over time. The oral uptake is rapid with a T_maxmax of 0.5 h and bioavailability F = 44% indicates very good absorption from the gut^[1].