CZC24832

CZC24832 is a highly selective and potent PI3Kγ inhibitor (IC₅₀=27 nM) with apparent dissociation constants (K_d^app) of 19 nM. IC50 & Target: IC50: 27 nM (PI3Kγ), 1.1 μM (PI3Kβ), 8.194 μM (PI3Kδ)^[1]
Kdapp: 19 nM (PI3Kγ)^[1] In Vitro: CZC24832 is active in PI3Kγ-dependent cellular C5a-induced AKT Ser473 phosphorylation (IC₅₀=1.2 μM) and N-formyl-methionine-leucinephenylalanine (fMLP)-induced neutrophil migration assays (IC₅₀=1.0 μM)^[1]. In Vivo: CZC24832 shows suitable pharmacokinetic properties including low clearance (0.84 L per h per kg body weight) and high oral bioavailability (37%), thus allowing further characterization of the inhibitor in rodent models of inflammation. In an IL-8-dependent air pouch model, CZC24832 shows a dose-dependent reduction of granulocyte recruitment (80% inhibition at 10 mg per kg body weight) consistent with the degree of inhibition observed in PI3Kγ-null mice. Mice treated orally with 10 mg CZC24832 per kg body weight twice per day show a substantial decrease of bone and cartilage destruction (53% reduction by histopathological analysis) as well as of overall clinical parameters (38% reduction)^[1].