"目录号: HY-13685
PI3K/Akt/mTORAnti-infection-
Miltefosine 是一种PI3K/Akt抑制剂，大大减少HIV-1从病毒感染的巨噬细胞产生。
AktHIV
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生物活性
Description
Miltefosine is aPI3K/Aktinhibitor, dramatically reducesHIV-1production 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 IC50of about 7 μM. Inhibition is competitive with regard to phosphatidylserine with a Kiof 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
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
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
NCT00696969
Drugs for Neglected Diseases
Visceral Leishmaniasis
June 2008
Phase 3
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References
[1].Chugh P, et al. Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy. Retrovirology. 2008 Jan 31;5:11.
[2].Uberall F, et al. Hexadecylphosphocholine inhibits inositol phosphate formation and protein kinase C activity. Cancer Res. 1991 Feb 1;51(3):807-12.
[3].Bhatt AP, et al. Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas. Blood. 2010 Jun 3;115(22):4455-63.
[4].Eissa MM, et al. Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study. PLoS One. 2015 Nov 17;10(11):e0141788.