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].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human PC3 cells	-	Growth inhibition assay	72 h	Growth inhibition of human PC3 cells after 72 hrs, IC50=0.011 μM	21763134
  MDA-MB-361 cells	-	Cytotoxicity assay	-	Cytotoxicity against human MDA-MB-361 cells, IC50=0.004 μM	20166697
  MDA-MB-361 cells	-	Function assay	-	Inhibition of Akt T308 phosphorylation in human MDA-MB-361 cells by Western blotting, IC50=0.008 μM	20166697

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• 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

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02626507	Breast Cancer	Phase 1	Recruiting	March 2019	United States, New York ... more >> Hoffman Oncology Recruiting Bronx, New York, United States, 10469 Contact: Anthony Hoffman, MD    718-655-1005    Doctor@hoffmanoncology.com Collapse <<
  NCT01925274	Metastatic Colorectal Cancer	Phase 2	Terminated(Enrollment to the s... more >>tudy was terminated on 11Nvo2014 due to slow recruitment. There were no safety or efficacy issues that contributed to this decision.) Collapse <<	-	United States, California ... more >> CBCC Global Research, Inc. at Comprehensive Blood and Cancer Center Bakersfield, California, United States, 93309 Drug Management Only: UCLA West Medical Pharmacy, Att: Steven L Wong, Pharm D Los Angeles, California, United States, 90095-7349 Drug Management Only: UCLA West Medical Pharmacy Los Angeles, California, United States, 90095-7349 UCLA West Medical Pharmacy Los Angeles, California, United States, 90095-7349 Regulatory Management Only: TRIO-US Central Administration Los Angeles, California, United States, 90095 TRIO-US Central Administration (Regulatory Management only) Los Angeles, California, United States, 90095 TRIO_US Los Angeles, California, United States, 90095 West Valley Hematology/Oncology Med Group Northridge, California, United States, 91328 United States, Missouri Siteman Cancer Center - West County Creve Coeur, Missouri, United States, 63141 Barnes-Jewish Hospital Saint Louis, Missouri, United States, 63110 Drug Shipping Address: Washington University Infusion Center Pharmacy Saint Louis, Missouri, United States, 63110 Washington University School of Medicine Saint Louis, Missouri, United States, 63110 Siteman Cancer Center - South County Saint Louis, Missouri, United States, 63129 Siteman Cancer Center - St Peters Saint Peters, Missouri, United States, 63376 United States, Nevada Regulatory Office: Comprehensive Cancer Centers of Nevada Henderson, Nevada, United States, 89014 Comprehensive Cancer Centers of Nevada Henderson, Nevada, United States, 89052 Comprehensive Cancer Centers of Nevada Henderson, Nevada, United States, 89074 Comprehensive Cancer Centers of Nevada Las Vegas, Nevada, United States, 89128 Comprehensive Cancer Centers of Nevada Las Vegas, Nevada, United States, 89148 Comprehensive Cancer Centers of Nevada Las Vegas, Nevada, United States, 89169 United States, New York Roswell Park Cancer Institute Buffalo, New York, United States, 14263 United States, Washington Kadlec Clinic Hematology and Oncology Kennewick, Washington, United States, 99336 Kadlec Medical Center Richland, Washington, United States, 99352 Outpatient Imaging Center Richland, Washington, United States, 99352 Spokane Valley Cancer Center Spokane Valley, Washington, United States, 99216 Medical Oncology Associates, PS Spokane, Washington, United States, 99208 Japan Aichi cancer center central hospital Nagoya, Aichi, Japan, 464-8681 National Cancer Center Hospital East Kashiwa, Chiba, Japan, 277-8577 Korea, Republic of National Cancer Center Goyang-si, Gyeonggi-do, Korea, Republic of, 410-769 Seoul National University Hospital / Department of Internal Medicine Seoul, Korea, Republic of, 110-744 Samsung Medical Center Seoul, Korea, Republic of, 135-710 Asan Medical Center Seoul, Korea, Republic of, 138-736 Spain Hospital General Universitario Gregorio Marañón Madrid, Spain, 28009 Collapse <<
  NCT01925274	-	-	Terminated(Enrollment to the s... more >>tudy was terminated on 11Nvo2014 due to slow recruitment. There were no safety or efficacy issues that contributed to this decision.) Collapse <<	-	-

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• 参考文献

• [1] Venkatesan AM, Dehnhardt CM, et al. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem. 2010 Mar 25;53(6):2636-45.

  [2] Zhao HF, Wang J, et al. Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development. Mol Cancer. 2017 Jun 7;16(1):100.