生物活性

• 靶点

  mTOR IC50:1.6nM

  PI3Kα IC50:0.4nM

  PI3Kγ IC50:5.4nM

• 描述PI3Ks are lipid kinases that phosphorylate PIP2 to PIP3. The catalytic subunits of class IA PI3Ks consists of PI3Kα, PI3Kβ and PI3Kδ isoforms. Among these isoforms, PIK3CA encoding the PI3Kα subunit, is mutated and/or overexpressed in breast, ovarian, colorectal, glioblastoma, and gastric cancers. The protein mTOR is one of the PI3K related kinases (PIKKs) which share a conserved kinase domain with PI3Ks. PI3K/Akt/mtor signaling is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. Gedatolisib, also called as PF-05212384 or PKI-587, is a highly potent PI3K/mTOR dual inhibitor with IC50 of 0.4 nM, 5.4 nM and 1.6 nM (measured by fluorescent polarization) on PI3Kα, PI3Kγ and mTOR, respectively. In vitro, Gedatolisib inhibits pAkt-T308 (IC50=8 nM) and pAkt-S473 (IC50 <10nM), as well as induces apoptosis in MDA-361 cells. Meanwhile, the phophorylation of Akt kinase effector (like proteins GSK3 kinase, ENOS and PRAS40) and mTORC1 effector (like p70S6K and 4EBP1 phosphorylation) can be suppressed by Gedatolisib at concentrations less than 30 nM. Administration of Gedatolisib i.v. at 20 mg/kg on an intermittent regimen (days 1, 5, 9) can regress large staged (∼900 mm3) tumors in MDA-361 tumor model^[1]. Up to now, Gedatolisib is used in the clinical trial study of Breast, endometrial, colorectal, ovarian, and H&N cancers, NSCLC, SCLC, AML^[2].
• 作用机制PKI-587 can dock in the ATP binding site of PI3K and form the critical hinge region hydrogen-bond to Val851 through a morpholine oxygen^[1].

• 动物研究
  剂量	Mice[1] (i.v.): min = 3 mg/kg, max = 30 mg/kg
  给药途径	i.v.
  动物药代数据	Animal Nude mice[1] T1/2 14.4 h Vss 7.2 L/kg C0 48523 ng/ml AUC0-inf 57927 h·ng/mL AUClast 42593 h·ng/mL MRT 16.7 h Clp 7 (mL/min)/kg