1. PI3K/Akt/mTOR
    Anti-infection
  2. Akt
    HIV

Miltefosine (Synonyms: HePC; Hexadecyl phosphocholine)

Cat. No.: HY-13685 Purity: >98.0%
Data Sheet SDS Handling Instructions

Miltefosine is a PI3K/Akt inhibitor, dramatically reduces HIV-1 production from long-living virus-infected macrophages.

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Miltefosine Chemical Structure

Miltefosine Chemical Structure

CAS No. : 58066-85-6

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Description

Miltefosine is a PI3K/Akt inhibitor, dramatically reduces HIV-1 production from long-living virus-infected macrophages.

IC50 & Target

PI3K/Akt[1]

In Vitro

Treatment of HIV-1 infected macrophages with Miltefosine inhibits the recruitment of PH-AktGFP to the plasma membrane. Since Miltefosine inhibits Akt through mimicry of the PH domain, it is likely that Miltefosine binds to PIP3, blocking the recruitment of PH-Akt to the membrane[1]. Miltefosine (HePC) inhibits protein kinase C (PKC) from NIH3T3 cells in cell-free extracts with a IC50 of about 7 µM. Inhibition is competitive with regard to phosphatidylserine with a Ki of 0.59 µM[2]. Miltefosine is an alkylphospholipid that inhibit activation of Akt. Miltefosine is a direct inhibitor of Akt, and induces dose-dependent inhibition of primary effusion lymphoma (PEL) in culture and also inhibits the downstream targets of Akt, such as mTOR, leading to reduced phosphorylation and activation of S6K and S6. Importantly, Miltefosine also inhibits Akt targets that are not part of the mTOR pathway, eg, FOXO1, and are therefore expected to have a greater therapeutic impact than mTORC1 inhibitors alone[3].

In Vivo

Mice are randomized into groups of 5 and injected intraperitoneally 5 days a week with 50 mg/kg of either Miltefosine or Perifosine dissolved in PBS, or equivalent volume of vehicle (PBS). Both Miltefosine and Perifosine inhibit the growth rate of tumors compared with vehicle-treated mice. By day 14 after treatment, there is an approximately 50% decrease in average tumor volume in Perifosine- and Miltefosine-treated mice, compared with vehicle-treated mice (P<0.04). Tumor growth is also significantly retarded (P<0.04 for Perifosine and P≤0.055 for Miltefosine by linear mixed-effects model analysis). Immunohistochemical analyses display an overall reduction in staining for phosphorylated ribosomal S6 protein in tumor sections from Miltefosine- and Perifosine-treated mice compared with the PBS-treated mice. This reduced phosphorylation correlated with the delay in tumor progression in drug-treated animals[3].

Clinical Trial
NCT Number Sponsor Condition Start Date Phase
NCT01462500 Centro Internacional de Entrenamiento e Investigaciones Médicas|Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) Cutaneous Leishmaniasis October 2011 Phase 4
NCT02687971 Drugs for Neglected Diseases Cutaneous Leishmaniasis December 2016 Phase 2
NCT02427308 Knight Therapeutics (USA) Inc Leishmaniasis or Other Uses of Miltefosine July 2015
NCT02193022 International Centre for Diarrhoeal Disease Research, Bangladesh|Thrasher Research Fund Post Kala Azar Dermal Leishmaniasis July 2014 Phase 3
NCT02429518 Knight Therapeutics (USA) Inc Mucocutaneous Leishmaniasis December 2015
NCT02431429 Knight Therapeutics (USA) Inc Mucocutaneous Leishmaniasis July 2015
NCT00371995 Banaras Hindu University|Rajendra Memorial Research Institute of Medical Sciences Visceral Leishmaniasis October 2007 Phase 2
NCT00487253 Centro Internacional de Entrenamiento e Investigaciones Médicas|Instituto Colombiano para el Desarrollo de la Ciencia y la Tecnología (COLCIENCIAS)|INS|Instituto Nacional de Dermatología Centro dermatológico Federico Lleras Acosta Cutaneous Leishmaniasis July 2007 Phase 3
NCT01380301 Foundation Fader|AB Foundation Cutaneous Leishmaniasis March 2007 Phase 2
NCT03023111 Hospital Universitário Professor Edgard Santos|Oswaldo Cruz Foundation Cutaneous Leishmaniasis March 2017 Phase 3
NCT02429505 Knight Therapeutics (USA) Inc Leishmaniasis July 2015
NCT01050907 Knight Therapeutics (USA) Inc Mucosal Leishmaniasis|Cutaneous Leishmaniasis May 2010 Phase 2
NCT02011958 Drugs for Neglected Diseases|Medecins Sans Frontieres, Netherlands|London School of Hygiene and Tropical Medicine|Addis Ababa University|Institute of Tropical Medicine, Belgium|Slotervaart Hospital|University of Gondar Visceral Leishmaniasis July 2014 Phase 3
NCT00471705 Universidad de Antioquia Cutaneous Leishmaniasis June 2006 Phase 3
NCT01377974 Brasilia University Hospital Leishmaniasis|Leishmaniasis, Mucocutaneous July 2009 Phase 2
NCT00600548 Hospital Universitário Professor Edgard Santos|Conselho Nacional de Desenvolvimento Científico e Tecnológico|Ministerio de Ciencia e Innovación, Spain|Ministério da Saúde|AEterna Zentaris Treatment of Cutaneous Leishmaniasis in Brazil. July 2007 Phase 2
NCT00373568 AB Foundation Leishmaniasis April 2005 Phase 1|Phase 2
NCT02431143 Drugs for Neglected Diseases Visceral Leishmaniasis May 2015 Phase 2
NCT02530697 University of Brasilia Leishmaniasis August 2015 Phase 2
NCT01380314 Foundation Fader Cutaneous Leishmaniasis March 2008 Phase 2
NCT03129646 Drugs for Neglected Diseases|The Netherlands Cancer Institute|The Institute of Endemic Diseases (IEND), University of Khartoum|Kenya Medical Research Institute|Makerere University|University of Gondar Visceral Leishmaniasis August 1, 2017 Phase 3
NCT01122771 Drugs for Neglected Diseases|Shaheed Surhawardy Medical College and Hospital|International Centre for Diarrhoeal Disease Research, Bangladesh Visceral Leishmaniasis May 2010 Phase 3
NCT00233545 AB Foundation Cutaneous Leishmaniasis September 2005 Phase 2
NCT01635777 AB Foundation|World Health Organization PKDL July 2007 Phase 2
NCT00537953 Centro de Investigaciones Bioclínicas de la Fundación Fader Cutaneous Leihmaniasis Phase 2
NCT01067443 Drugs for Neglected Diseases|Gilead Sciences|Paladin Laboratories Inc Primary Visceral Leishmaniasis March 2010 Phase 2
NCT00378495 AB Foundation|AEterna Zentaris Kala Azar April 2005 Phase 1|Phase 2
NCT00373776 AB Foundation Leishmaniasis April 2004 Phase 1|Phase 2
NCT01170949 Marcus Maurer|Charite University, Berlin, Germany Chronic Urticaria September 2008 Phase 2
NCT01975051 International Centre for Diarrhoeal Disease Research, Bangladesh|University of Nagasaki. Post-kala-azar Dermal Leishmaniasis January 2013 Phase 4
NCT00370825 Banaras Hindu University Visceral Leishmaniasis September 2006 Phase 2
NCT00523965 Banaras Hindu University|Drugs for Neglected Diseases|Rajendra Memorial Research Institute of Medical Sciences Leishmaniasis, Visceral September 2007 Phase 3
NCT00351520 Tehran University of Medical Sciences|World Health Organization Cutaneous Leishmaniasis May 2006 Phase 3
NCT00696969 Drugs for Neglected Diseases Visceral Leishmaniasis June 2008 Phase 3
NCT02366884 Dr. Frank Arguello Cancer Clinic|Instituto de Ciencia y Medicina Genomica, Torreon, Coah. Mexico www.institutodeciencia.com Neoplasms July 2011 Phase 2
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References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
1 mM 2.4536 mL 12.2678 mL 24.5357 mL
5 mM 0.4907 mL 2.4536 mL 4.9071 mL
10 mM 0.2454 mL 1.2268 mL 2.4536 mL
Kinase Assay
[3]

Levels of enzymatically active caspase-3 are quantified using the ApoAlert Caspase Fluorescent assay kit. Briefly, 1×106 BC-1 PEL cells are treated with 50 μM Miltefosine, 50 μM Perifosine, or 20 nM NVP-BEZ235, as well as the respective vehicle controls. Cells are harvested and lysed 12 hours later. Equivalent micrograms of cell lysate for all samples are incubated with a fluorogenic caspase-3 substrate (DEVD-AFC). Cleavage of DEVD by caspase-3 releases AFC, the fluorescence of which is measured using a FLUOstar OPTIMA fluorometer, with excitation and emission filter wavelengths set to 400 and 505 nm, respectively[3].

Cell Assay
[2]

Miltefosine (HePC) is prepared as a stock solution containing 10 mM Miltefosine in 20 mM Tris-HCI, pH 7.4, and stored (-20°C), and then diluted before use[2].

NIH3T3 cells are grown in DMEM supplemented with 10% FCS in a humidified atmosphere of 95% air with 5% CO2. Cells are plated on 35-mm culture dishes (6-well plates) at 0.5-0.8×105 cells/well. Growth is established for 18-24 h and the cell number of representative wells is determined (time 0). The experiments are started by addition of fresh prepared solution of Miltefosine at given concentrations to the cells or equal volumes of Tris-HCI to control cells. After incubation for 60 h, cells are counted with an electronic counter. Cellular multiplication is calculated[2].

Animal Administration
[3][4]

Miltefosine is dissolved in PBS (Mice)[3].
Miltefosine (MFS) is prepared as an aqueous solution or MFS-lipid nanocapsules (LNCs) dispersion (Rat)[4].

Mice[3]
PEL cells are washed in ice-cold phosphate buffered saline, counted, and diluted in 100 μL of PBS mixed with 100 μL of growth factor-depleted Matrigel. A total of 1×105 to 7.5×105 BC-1 cells are injected subcutaneously into the right flank of NOD.CB17-Prkdcscid/J or CB17-Prkdcscid/J mice. The mice are monitored on alternate days for development of palpable tumors (2 mm3), at which point drug or vehicle treatments are initiated, and are administered either intraperitoneally (Perifosine) or by oral gavage (Rosiglitazone, NVP-BEZ235) 5 days a week. Groups of 5 to 7 mice are used to generate PEL tumors and treated with either vehicle or drug cocktail. Each biologic experiment is repeated multiple times. For Rosiglitazone, 0.25% methylcellulose is used as vehicle, and 30 mg/kg or 60 mg/kg Rosiglitazone is suspended in methylcellulose. For Perifosine and Miltefosine, PBS is used as a vehicle and 50 mg/kg Perifosine or Miltefosine is dissolved in PBS. For NVP-BEZ235, the compound is dissolved in a 1:9 vol/vol mixture of 1-methyl-2-pyrrolidone and polyethylene glycol 300. A dose of 40 mg/kg NVP-BEZ235 or equal volume of the vehicle is administered. Tumor diameters are measured using digital calipers, and tumor volume is calculated. The tumors are excised and fixed in formalin. Statistical analyses are performed using linear model fit by maximum likelihood with individual animals treated as random effect.
Rat[4]
Male Sprague-Dawley rats (weight 270-290 g) are divided into five groups (n=5). Rats in the treatment groups are administered a single 10 mg/kg oral dose of Miltefosine (MFS) either as an aqueous solution or MFS-LNCs dispersion by gastric gavage. This dose is equivalent to the 20 mg/kg Miltefosine dose administered to mice in the preclinical study after correction for rats. Following administration, blood samples are collected via the orbital plexus under anesthesia at time intervals of 0.5, 1, 2, 4, 7, 10, 24, 48, 72 and 216 h in Eppendorf tubes containing EDTA. Blood samples are then centrifuged immediately at 4000 rpm for 10 min. Plasma samples are frozen and maintained at -80°C pending analysis.

References
M.Wt

407.57

Formula

C₂₁H₄₆NO₄P

CAS No.

58066-85-6

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

DMSO: < 4.4 mg/mL

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

Purity: >98.0%

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