CZC24832 is a selective phosphoinositide 3-kinase γ (PI3Kγ) inhibitor. CZC24832 regulates interleukin-17-producing T helper cell (TH17) differentiation by PI3Kγ thus making CZC24832 a potential treatment for inflammatory and autoimmune diseases.
CZC24832 is a potent and selective inhibitor of phosphoinositide 3-kinase γ (PI3Kγ) with Kd app of 19 nM. CZC24832 is said to be the first selective PI3Kγ inhibitor with efficacy in in vitro and in vivo models of inflammation. CZC24832 strongly inhibited T-cell interleukin 17A (IL-17A) production by inhibiting expression of retinoic acid receptor–related orphan receptor γt (RORγt), a transcription factor th at drives TH17 differentiation, showing a new role for PI3Kγ.
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].
PI3Kγ: 27 nM (IC50); PI3Kβ: 1.1 μM (IC50); PI3Kδ: 8.194 μM (IC50)
