生物活性

• 靶点	PI3Kγ IC50:16nM

• 描述PI3Ks are divided into three classes (I, II, and III) based on substrate specificity, sequence homology, and types of regulatory subunits. Class I PI3Ks are further divided into Class IA and Class IB. Class IB of PI3Ks containing the only member, PI3Kγ, is activated primarily by G-protein coupled receptors. The PI3Kγ isoform is mainly expressed in immune cells. Preclinical studies suggest that PI3Kγ inhibition in tumor-associated myeloid cells may be effective to prevent tumor growth. IPI-549 is a potent inhibitor of PI3Kγ (IC50 = 16 nM, measured by Promega ADP-Glo Max assay kit) with >100-fold selectivity over other lipid and protein kinases. IPI-549 shows excellent PI3Kγ potency (IC50 = 1.2 nM) and selectivity against other Class I PI3K isoforms (>146-fold) measured by cellular phospho-AKT inhibition assays in SKOV-3, 786-O, RAW 264.7, and RAJI cells. Also, IPI-549 inhibited PI3Kγ-dependent BMDM migration in a dose-dependent manner in vitro. 0.1 - 3 mg/kg oral treatment of IPI-549 significantly reduced neutrophil migration in a dose-dependent manner while a significant inhibition of PI3Kγ can be observed in the mouse air pouch model. IPI-549 is currently in Phase 1 clinical evaluation of advanced solid tumors^[1].

• 动物研究
  剂量	Mice: 15 mg/kg[2] (p.o.), 3 mg/kg[3] (i.p.)
  给药途径	p.o, i.p.
  动物药代数据	Animal Mice[1] Rats[1] Dogs[1] Monkeys[1] Dose 1 mg/kg 1 mg/kg 0.5 mg/kg 0.5 mg/kg Administration i.v. i.v. i.v. i.v. T1/2 3.2 h 4.4 h 6.7 h 4.3 h Vss 0.8 L/kg 1.2 L/kg 1.3 L/kg 1.3 L/kg CL 3.6 ml/min/kg 4.4 ml/min/kg 2.8 ml/min/kg 4.3 ml/min/kg F 0.88 0.57 0.65 0.31