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    AZITHROMYCIN AND ROXITHROMYCIN DERIVTIVES AS SENOLYTIC DRUGS
    1.
    发明公开
    AZITHROMYCIN AND ROXITHROMYCIN DERIVTIVES AS SENOLYTIC DRUGS 审中-公开

    公开(公告)号：US20240180944A1

    公开(公告)日：2024-06-06

    申请号：US18442204

    申请日：2024-02-15

    Applicant: LUNELLA BIOTECH, INC.

    Inventor： Federica SOTGIA ,  Michael P. LISANTI

    IPC: A61K31/7048 ,  A61K31/7052 ,  A61K45/06

    CPC classification number: A61K31/7048 ,  A61K31/7052 ,  A61K45/06

    Abstract: This disclosure describes the use of azithromycin, roxithromycin, and telithromycin, including derivatives thereof, as senolytic drugs. BrdU was used to induce senescence in model human fibroblast cell lines. Also disclosed are methods for screening compounds for senolytic activity. The SRB assay was used to measure cell viability through protein content. Azithromycin roxithromycin, and telithromycin, clinically-approved pharmaceuticals, were found to be senolytic drugs. However, the closely-related parent compound, erythromycin, showed no senolytic activity. Azithromycin strongly induced both aerobic glycolysis and autophagy in human fibroblasts, but showed bi-phasic effects including on mitochondrial oxygen consumption rates with inhibitory activity at 50 μM and stimulatory activity at 100 μM. The xCELLigence real-time assay system showed that azithromycin preferentially targets senescent cells, removing approximately 97% (nearly a 25-fold reduction in senescent cells).

    MYRISTOYL DERIVATIVES OF 9-AMINO-DOXYCYCLINE FOR TARGETING CANCER STEM CELLS AND PREVENTING METASTASIS
    2.
    发明公开
    MYRISTOYL DERIVATIVES OF 9-AMINO-DOXYCYCLINE FOR TARGETING CANCER STEM CELLS AND PREVENTING METASTASIS 审中-公开

    公开(公告)号：US20230174464A1

    公开(公告)日：2023-06-08

    申请号：US17924614

    申请日：2021-05-13

    Applicant: LUNELLA BIOTECH, INC.

    Inventor： Michael P. LISANTI ,  Federica SOTGIA ,  Béla OZSVARI ,  Jussi KANGASMETSA

    IPC: C07C237/26 ,  A61P35/04 ,  A61P31/04

    CPC classification number: C07C237/26 ,  A61P35/04 ,  A61P31/04

    Abstract: Disclosed are 9-amino-doxycycline derivatives that target cancer stem cells and inhibit cancer metastasis. These compounds selectively target CSCs, potently inhibit tumor cell metastasis in vivo, with little or no toxicity, and minimize the risk of driving antibiotic resistance. In one embodiment, a 14 carbon fatty acid moiety is covalently attached to the free amino group of 9-amino-doxycycline. The resulting “Doxy-Myr” conjugate is over 5-fold more potent than doxycycline for inhibiting the anchorage-independent growth of MCF7 CSCs. Doxy-Myr did not affect the viability of the total MCF7 cancer cell population or normal fibroblasts grown as 2D-monolayers, showing remarkable selectivity for CSCs. Doxy-Myr did not show antibiotic activity, against Escherichia coli and Staphylococcus aureus. Conjugates having either longer (16 carbon; palmitic acid) or shorter (12 carbon; lauric acid) fatty acid chain lengths had similar activity.

    Energetic cancer stem cells (e-CSCs): a new hyper-metabolic and proliferative tumor cell phenotype, driven by mitochondrial energy
    3.
    发明授权
    Energetic cancer stem cells (e-CSCs): a new hyper-metabolic and proliferative tumor cell phenotype, driven by mitochondrial energy 有权

    公开(公告)号：US11441195B2

    公开(公告)日：2022-09-13

    申请号：US17254157

    申请日：2019-06-19

    Applicant: LUNELLA BIOTECH, INC.

    Inventor： Michael P. Lisanti ,  Federica Sotgia ,  Marco Fiorillo

    IPC: A61K49/00 ,  C12Q1/6886 ,  A61K31/03 ,  A61K31/519 ,  A61K45/06

    Abstract: This disclosure describes the characteristics of the “energetic” cancer stem cell (e-CSC) phenotype. This distinct sub-population of cancer stem cells (CSCs) has a unique energetic profile compared to bulk CSCs, being more glycolytic, having higher mitochondrial mass and elevated oxidative metabolism. e-CSCs also show an increased capacity to undergo cell cycle progression, enhanced anchorage-independent growth, and ALDH-positivity. The e-CSC phenotype presents new targets for cancer therapeutics, and in particular the anti-oxidant response, mitochondrial energy production, and mitochondrial biogenesis of e-CSCs makes them highly susceptible to mitochondrial inhibitors that target e-CSC anti-oxidant response, mitochondrial energy production, and mitochondrial biogenesis. Gene products for e-CSCs are disclosed, as well as classes of mitochondrial inhibiting therapeutic agents. Also disclosed are methods for identifying and separating e-CSCs from bulk cell populations.

    AZITHROMYCIN AND ROXITHROMYCIN DERIVTIVES AS SENOLYTIC DRUGS
    4.
    发明申请
    AZITHROMYCIN AND ROXITHROMYCIN DERIVTIVES AS SENOLYTIC DRUGS 有权

    公开(公告)号：US20210275560A1

    公开(公告)日：2021-09-09

    申请号：US17282212

    申请日：2019-10-02

    Applicant: LUNELLA BIOTECH, INC.

    Inventor： Federica SOTGIA ,  Michael P. LISANTI

    IPC: A61K31/7048 ,  A61K31/7052 ,  A61K45/06

    Abstract: This disclosure describes the use of azithromycin, roxithromycin, and telithromycin, including derivatives thereof, as senolytic drugs. BrdU was used to induce senescence in model human fibroblast cell lines. Also disclosed are methods for screening compounds for senolytic activity. The SRB assay was used to measure cell viability through protein content. Azithromycin roxithromycin, and telithromycin, clinically-approved pharmaceuticals, were found to be senolytic drugs. However, the closely-related parent compound, erythromycin, showed no senolytic activity. Azithromycin strongly induced both aerobic glycolysis and autophagy in human fibroblasts, but showed bi-phasic effects including on mitochondrial oxygen consumption rates with inhibitory activity at 50 μM and stimulatory activity at 100 μM. The xCELLigence real-time assay system showed that azithromycin preferentially targets senescent cells, removing approximately 97% (nearly a 25-fold reduction in senescent cells).

    ANTI-MITOCHONDRIAL INHIBITORS FOR ONCOGENIC RAS AND MYC
    5.
    发明申请
    ANTI-MITOCHONDRIAL INHIBITORS FOR ONCOGENIC RAS AND MYC 审中-公开

    公开(公告)号：US20200292551A1

    公开(公告)日：2020-09-17

    申请号：US16753493

    申请日：2018-10-11

    Applicant: LUNELLA BIOTECH, INC.

    Inventor： Michael P. LISANTI ,  Federica SOTGIA

    IPC: G01N33/574 ,  A61K31/138 ,  G01N33/50 ,  G01N33/543

    Abstract: The present disclosure relates to a Proteomics-to-Genomics approach allows for in silico validation of biomarkers and drug targets. Biomarkers having high prognostic value in predicting cancer patient populations that may benefit from mitochondrial biogenesis inhibitor therapy may be identified under the present approach. Also disclosed are methods for identifying candidates for anti-mitochondrial therapy, and in particular mitochondrial biogenesis inhibitor therapy. Diagnostic kits including reagents for determining transcripts or probes of high prognostic value are also disclosed. Additionally, mitochondrial biogenesis inhibitors may be used as anti-cancer agents for diverse oncogenic stimuli, including for example, c-MYC and H-Ras oncogenes, as well as environmental stimuli such as, for example rotenone.

    MITOCHONDRIAL ATP INHIBITORS TARGETING THE GAMMA SUBUNIT PREVENT METASTASIS
    9.
    发明申请
    MITOCHONDRIAL ATP INHIBITORS TARGETING THE GAMMA SUBUNIT PREVENT METASTASIS 有权

    公开(公告)号：US20250049823A1

    公开(公告)日：2025-02-13

    申请号：US18722474

    申请日：2022-12-22

    Applicant: LUNELLA BIOTECH, INC.

    Inventor： Michael P. LISANTI ,  Federica SOTGIA ,  Marco FIORILLO ,  Jussi KANGASMETSA ,  Marta MAURO LIZCANO

    IPC: A61K31/675 ,  A61P35/04 ,  C07F9/60

    Abstract: High ATP production by the mitochondrial ATP-synthase is a new therapeutic target for anti-cancer therapy, especially for preventing tumor progression. A mitochondrial-related gene signature for metastasis is described, which features the gamma-subunit of the mitochondrial ATP-synthase (ATP5F1C). Knock-down of ATP5F1C expression significantly reduces ATP-production, 3D anchorage-independent growth and cell migration. Administration of the Bedaquiline, or a Bedaquiline derivative with a TPP moiety, down-regulates ATP5F1C expression in vitro and prevents spontaneous metastasis in vivo. Mitochondrial ATP5F1C is a promising new biomarker and molecular target for future drug development, for the prevention of metastatic disease progression.

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