生物活性

• 靶点

  PI3Kα IC50:0.469nM

  PI3Kβ IC50:3.72nM

• 描述PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) participate in a diverse array of process, including the regulation of cellular survival, differentiation and stem cell-like properties, growth, proliferation, metabolism, migration, and angiogenesis^[1]. The isoform PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ are the catalytic subunits of class I PI3Ks. Copanlisib, also called as BAY 80-6946, is a potent pan-class I PI3K inhibitor with IC50 of 0.5, 3.7, 6.4, and 0.7 nM (measured by Biochemical lipid kinase assays) for PI3Kα/β/γ/δ , respectively and shows weaker activity against mTOR with an IC50 of 45 nM. In rat ELT3 cells (a PI3K-independent activation of mTORC1 due to TCS2 deficiency), 5 nM of Copanlisib can inhibit PI3K-mediated AKT phosphorylation completely, whereas only a minor reduction of S70S6K levels and no effect at all on p-4E-BP1 at a concentration of 500 nM can be observed. Thus, Copanlisib is not a dual PI3K/mTOR inhibitor. Copanlisib has anti-proliferative activity against a subset of human cancer cell lines, particularly PIK3CA mutated and/or over-expressed cells. Meanwhile, Copanlisib can induce apoptosis and cell death in both anti-HER2–sensitive and -resistant, PI3K-mutant breast tumor cells. Copanlisib has a good pharmacokinetic property with a high plasma-free fraction across all species tested (35% in rats, 14% in mice, 33% in dogs, and 16% in humans). In in-vivo study, Copanlisib of 6 mg/kg i.v. bolus dose inhibited pAKT-Ser473 in tumors more than 90% at 24 hours after intravenous dosing and remained suppressed for 48 to 72 hours in nude rats bearing H460 human non–small cell lung carcinoma (NSCLC) xenografts, which shows its good pharmacodynamic. Copanlisib also shows efficacious antitumor activity, for administration of 14 mg/kg every second day for a total of 10 days can produce TGI rates of 88% in the NSCLC model and 71% in the breast cancer model^[2]. Up to now, a phase III study of copanlisib versus placebo in rituximab-refractory iNHL has completed enrollment^[3].
• 作用机制The dihydroimidazole structure of Copanlisib can bound to the ATP binding site of PI3Ks^[4].

• 动物研究
  剂量	Mice[5]: 6 mg/kg (i.p.)
  给药途径	i.p.
  动物药代数据	Animal Mice[2] Rats[2] Administration i.v. i.v. T1/2 0.7 h 6.0 h Vss 12.9 L/kg 32 L/kg AUC Norm0-inf 0.063 kg·h/L 0.253 kg·h/L CL 15.97 L/kg·h 3.95 L/kg·h