生物活性

• 靶点	Akt IC50:4.7μM

• 描述AKT is the central node of PI3K/AKT/mTOR pathway. It has three functional domains -- a PH domain, a-helical linker domain and central kinase domain. The PH domain can interact with phospholipids produced by the actions of PI3K which serve to home AKT to the cell membrane and transfer to an active conformation^[1]. Perifosine (KRX-0401) is an alkylphospholipid-kind inhibitor of AKT. It can inhibit the binding of the AKT-PH domain to artificial membranes containing 3% PI(3,4)P2 with IC50 value of ~10 μM (measured by SPR) ^[2]. Treatment of perifosine on concentration of 5uM can decrease level of p-AKT-S473 and p-AKT-T308 in PC-3 cells. Stimulated Akt phosphorylation by serum, insulin, IGF-I, EGF, and PDGF was strongly inhibited by 5 μM perifosine for 30 min. Treatment of perifosine (5 μM) can inhibit the membrane localization of the PH domain of Akt^[3]. In vivo study shows that either oral daily (36 mg/kg/d) or weekly (250 mg/kg/week) administration of perifosine can significantly reduce MM tumor growth and increase survival compared with control group in mice^[4]. Clinical trials of perifosine treatment for cancer, including a phase 3 study for colorectal cancer, have been done (see in https://clinicaltrials.gov/).
• 作用机制Perifosine inhibits AKT by preventing its translocation from the cytosol to the inner leaflet of the plasma membrane.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  769-P	0-40 μM	Growth Inhibition Assay	72 h	IC50~5-10 μM	21644050
  769-P	0-20 μM	Growth Inhibition Assay	72 h	inhibits cell growth in a dose dependent manner	21644050
  786-0	0-40 μM	Growth Inhibition Assay	72 h	IC50~5 μM	21644050

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• 动物研究
  剂量	Mice (p.o.): min = 36 mg/kg[4], max = 200 mg/kg[6]
  给药途径	p.o.
  动物药代数据	Animal Nude mice[7] Dose 40 mg/kg Administration p.o. Cmax 5.7 μg/ml T1/2 137 ± 20 h CL 0.057 l/h/kg Tmax 22 h AUC 698 ± 19 μg/ml·h Vd 11.3 l/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
  NCT01555281	Multiple Myeloma	Phase 1 Phase 2	Active, not recruiting	December 2019	Italy ... more >> Istituto Europeo di Oncologia IEO Milano, Italy, 20141 University of Torino Torino, Italy, 10127 Switzerland Kantonsspital Aarau Aarau, Switzerland, 5001 Kantonsspital Baden Baden, Switzerland, 5404 Istituto Oncologico Svizzera Italiana IOSI Bellinzona, Switzerland, 6500 Inselspital Bern Bern, Switzerland, 3010 Kantonsspital Graubünden Chur, Switzerland, 7000 Kantonsspital Olten Olten, Switzerland, 4600 Kantonsspital St. Gallen St. Gallen, Switzerland, 9007 Regionalspital Thun, Switzerland, 3600 UniversitätsSpital Zürich Zürich, Switzerland, 8091 Collapse <<
  NCT00055380	Cancer	Phase 1	Completed	-	United States, Maryland ... more >> National Institute of Dental And Craniofacial Research (NIDCR) Bethesda, Maryland, United States, 20892 Collapse <<
  NCT00053794	Endometrial Cancer ... more >> Sarcoma Collapse <<	Phase 2	Completed	-	Canada, Alberta ... more >> Tom Baker Cancer Center - Calgary Calgary, Alberta, Canada, T2N 4N2 Canada, British Columbia British Columbia Cancer Agency - Vancouver Island Cancer Centre Vancouver, British Columbia, Canada, V5Z 4E6 Canada, Ontario Margaret and Charles Juravinski Cancer Centre Hamilton, Ontario, Canada, L8V 5C2 Cancer Care Ontario-London Regional Cancer Centre London, Ontario, Canada, N6A 4L6 Mount Sinai Hospital - Toronto Toronto, Ontario, Canada, M5G 1X5 Canada, Quebec Maisonneuve-Rosemont Hospital Montreal, Quebec, Canada, H1T 2M4 Collapse <<

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• 参考文献

• [1] Keane NA, Glavey SV, et al. AKT as a therapeutic target in multiple myeloma. Expert Opin Ther Targets. 2014 Aug;18(8):897-915.

  [2] Perifosine selectively inhibits binding of Akt PH domain to PtdIns(3,4)P2

  [3] Kondapaka SB, Singh SS, et al. Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther. 2003 Nov;2(11):1093-103.

  [4] Hideshima T, Catley L, et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood. 2006 May 15;107(10):4053-62. Epub 2006 Jan 17.

  [5] Meuillet EJ, et al. Novel inhibitors of AKT: assessment of a different approach targeting the pleckstrin homology domain. Curr Med Chem. 2011;18(18):2727-42.

  [6] Hennessy BT, Lu Y, et al. Pharmacodynamic markers of perifosine efficacy. Clin Cancer Res. 2007 Dec 15;13(24):7421-31.

  [7] Vink SR, Schellens JH, et al. Tumor and normal tissue pharmacokinetics of perifosine, an oral anti-cancer alkylphospholipid. Invest New Drugs. 2005 Aug;23(4):279-86.

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