生物活性

• 描述PI3K/AKT/mTOR pathway directly relates to cellular quiescence, proliferation, cancer, and longevity. There are eight PI3 kinases have been identified as classes IA, 1B, II, and III based on the sequence homology and substrate preference. Among them, class IA PI3K is composed of a heterodimer consisting of a 110 kDa catalytic subunit (p110α, p110β and p110δ) and an 85 kDa regulatory subunit^[1]. PI-103 is a dual inhibitor of Class IA PI3Ks (p110α/β/δ/γ with IC50 of 2 nM/3 nM/3 nM/15 nM determined using a scintillation proximity assay, respectively) and mTOR (IC50 = 30 nM), with less potent to DNA-PK (IC50 = 23 nM)^[1]. PI-103 is usually used in ACUTE LYMPHOBLASTIC LEUKEMIA study. It can inhibit PI3K/Akt and mTORC1 activity in MOLM14, OCI-AML3 and MV4-11 leukemic cell lines, which have constitutive activation of PI3K/Akt (p-Akt Ser 473 and p-FOXO3a Thr32), mTORC1 (p-P70S6K Thr389) signaling pathways, with no inhibition on ERK/MAPK (p-p42/44 ERK/MAPK Thr202/Tyr204). In AML blast cells, PI-103 inhibits both constitutive and growth factor-induced PI3K/Akt and mTORC1 activation, reverses the positive feedback of mTORC1 inhibition on PI3K/Akt and induces significant apoptosis^[2]. In glioma, PI‑103 induces autophagy and promotes cell survival by inhibiting mTOR activity. Conversely, PI‑103 can lead to apoptosis by combining with autophagy inhibitors like 3-ma or bafilomycin A1^[3].
• 作用机制PI-103 acts as an ATP-competitive inhibitor of PI3K (Class IA)^[4].

• 动物研究
  剂量	Mice[5] (i.p.): 10 mg/kg, 70mg/kg
  给药途径	i.p.
  动物药代数据	Animal Mice[6] Dose 2.5 mg/kg (i.v.) 50 mg/kg (i.p.) Administration i.v. i.p. Cmax 4168.8 nmol/L (i.v.) 6680.0 nmol/L (i.p.) T1/2 0.7 h (i.v.) 0.12 h (i.p.) CL 0.19 L/h (i.v.) 0.12 L/h (i.p.) AUClast 624.3 h·nmol/L (i.v.) 20549.0 h·nmol/L (i.p.) Tmax 0 h (i.v.) 0.25 h (i.p.) Vd 0.2 L (i.v.) 0.71 L (i.p.)