WO2021105761A1 - Compositions et leurs utilisations pour le traitement de cancers - Google Patents

Compositions et leurs utilisations pour le traitement de cancers Download PDF

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WO2021105761A1
WO2021105761A1 PCT/IB2020/000777 IB2020000777W WO2021105761A1 WO 2021105761 A1 WO2021105761 A1 WO 2021105761A1 IB 2020000777 W IB2020000777 W IB 2020000777W WO 2021105761 A1 WO2021105761 A1 WO 2021105761A1
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cancer
anticancer
pharmaceutically acceptable
chloroquine
derivatives
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Mojgan DJAVAHERI-MERGNY
Jennifer BEAUVARLET
Jean-Louis Mergny
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Institut National De La Santé Et De La Recherche Médicale (Inserm)
Centre National De La Recherche Scientifique (Cnrs)
Universite de Bordeaux
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Publication of WO2021105761A1 publication Critical patent/WO2021105761A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to the field of oncology, and more particularly relates to combinations, pharmaceutical compositions, or kit-of-parts, and their use for preventing and/or treating cancer diseases, and in particular, chemoresistant or potentially chemoresistant cancer diseases. BACKGROUND OF THE INVENTION
  • Cancer refers a group of diseases characterized by the development of abnormal cells that divide uncontrollably and can infiltrate and destroy normal body tissue. Cancer is the second-leading cause of death in the world. Numerous therapies, in particular chemotherapies, have been developed to treat the various cancer diseases. However, sometimes, cancer cells can overcome the efficacy of the anticancer agents and may become chemoresistant.
  • lysosomes are involved in resistance to anticancer agents.
  • One proposed mechanism is the sequestration of the anticancer agent into the lysosome which results in reduction of the accessibility of the drug to its cellular targets as well as of its effectiveness. This effect ultimately has been suggested to contribute to resistance to chemotherapy (Gong Y et al., J Pharmacol Exp Ther 2006; 316: 242-247; Herlevsen et al., Mol Cancer Ther 2007; 6: 1804-1813; Smith et al., Cancer Res 1992; 52: 4000 ⁇ 008; Zhitomirsky et al., Oncotarget 2015; 6: 1143-1156; Kroemer et al., Oncotarget 2017; 8: 112168-112169).
  • G-quadruplexes are four-stranded non-canonical nucleic acids secondary structures which form in guanine-rich DNA and RNA sequences. Many G-quadruplex forming sequences are found to be associated with cancer. Some compounds, named G-quadruplex interactive ligands (or G-quadruplex ligands, or G4 ligands, abbreviated as G4L) have been shown to strongly interact with G-quadruplex DNA and to inhibit cancer proliferation.
  • G4L G-quadruplex interactive ligands
  • Lysosomal dependent non-apoptotic cell death is of tremendous interest in cancer therapy as cancer cells often display defective apoptotic machinery rendering them resistant to therapy.
  • the present invention has for purpose to satisfy all or part of those needs.
  • the present invention relates to a combination comprising at least one anticancer G-quadruplex ligand and at least one lysosomotropic agent; or a pharmaceutically acceptable salt thereof.
  • the present invention lies on the discovery that chemoresistance, in particular lysosomal-induced chemoresistance, of cancer cells to anticancer G-quadruplex ligands can be removed or strongly reduced, or prevented, by a treatment combining at least one anticancer G-quadruplex ligand (anticancer G4L) with at least one lysosomotropic agent. It has been surprisingly observed that such a combination exerts, with an unexpected synergic effect, an apoptotic effect on cancer cells and chemoresistant cancer cells. More particularly, it has been surprisingly observed that such a combination can induce lysosomal membrane permeabilization into cancer cells, and trigger cancer cells death.
  • the inventors have unexpectedly found that the combination of an anticancer G4L, such as 20A or quarfloxin, and a lysosomotropic agent, such as chloroquine or Lys05, provokes a significant lysosomal membrane permeability and triggers a massive cell death in various cancer cell lines.
  • an anticancer G4L, such as 20A or quarfloxin, and a lysosomotropic agent, such as chloroquine or Lys05 can act synergistically to provoke a significant lysosomal membrane permeability.
  • an anticancer G4L such as 20A or quarfloxin
  • a lysosomotropic agent such as chloroquine or Lys05
  • an anticancer G4L such as 20A or quarfloxin
  • a lysosomotropic agent such as chloroquine or Lys05
  • a massive cell death in cervical cancer cells such as HeLa
  • lung adeno-carcinoma cells such as the A549 cell line
  • bone osteosarcoma epithelial cells such as U20S
  • PDX cells from lung cancer patients
  • an anticancer G4L such as 20A or quarfloxin
  • a lysosomotropic agent such as chloroquine or Lys05
  • the inventors have observed that combining an anticancer G4L, such as 20A or quarfloxin, and a lysosomotropic agent, such as chloroquine or Lys05, can synergistically act to induce cell death in cancer cells, such as cervical cancer cells or in lung adeno-carcinoma cells.
  • an anticancer G4L such as 20A or quarfloxin
  • a lysosomotropic agent such as chloroquine or Lys05
  • an anticancer G4L may be selected in the group consisting in triarylpyridines; fluoroquinolones and derivatives thereof; 2,6-diamidoanthraquinone and derivatives thereof; IZNP1 ; TH3; IZCZ-3; benzofuran and derivatives thereof; Tz1 ; furopyridazinone and derivatives thereof; GTC365; acridine and acridinium derivatives thereof; berberine and epiberberine; naphtalene diimides (NDI); quindoline; indoloquinolines; quinazolone derivatives; telomestatin; L1 H1 -70TD; cyanine derivatives; topotecan; porphyrin and porphyrazine derivatives thereof, such as N-methyl MesoPorphyrin IX (NMM) or TMPyP4; isaindigotone and derivatives thereof; SYUIQ-FM05;
  • an anticancer G4L may be selected among triarylpyridines; fluoroquinolones and derivatives thereof; or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a combination comprising at least one anticancer G-quadruplex ligand selected among triarylpyridines and fluoroquinolones and at least one lysosomotropic agent; or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a combination comprising at least one anticancer G-quadruplex ligand selected among triarylpyridines and at least one lysosomotropic agent; or a pharmaceutically acceptable salt thereof.
  • a triarylpyridine suitable for the invention may be compound 20A as disclosed in Smith et al., Org Biomol Chem. 2011 ; 9(17) :6154-62).
  • a fluoroquinolone or a derivative thereof suitable for the invention maybe quarfloxin or CX-5461 .
  • an anticancer G4L may be triarylpyridine 20A; quarfloxin; or a pharmaceutically acceptable salt thereof.
  • a lysosomotropic agent may be selected in the group consisting in chloroquine and derivatives thereof, such as oxychloroquine or hydroxychloroquine; nanaomycin; siomycin A; helenalin; Lys05; siramesine; GNS561 ; or a pharmaceutically acceptable salt thereof.
  • a lysosomotropic agent may be selected in the group consisting in chloroquine; oxychloroquine; hydroxychloroquine; Lys05; siramesine; GNS561 ; and in particular is chloroquine or Lys05; or a pharmaceutically acceptable salt thereof; and more particularly is chloroquine diphosphate or Lys05.
  • a lysosomotropic agent may be chloroquine; hydroxychloroquine; or a pharmaceutically acceptable salt thereof such as chloroquine or hydroxychloroquine diphosphate.
  • a lysosomotropic agent may be chloroquine; or a pharmaceutically acceptable salt thereof, such as chloroquine diphosphate.
  • a lysosomotropic agent may be Lys05.
  • an anticancer G4L may be a triarylpyridine or fluoroquinolone, or a derivative thereof, and a lysosomotropic agent may be chloroquine, hydroxychloroquine, or Lys05, or a pharmaceutically acceptable salt thereof.
  • an anticancer G4L may be a triarylpyridine; a fluoroquinolone or a derivative thereof; or a pharmaceutically acceptable salt thereo, and a lysosomotropic agent may be chloroquine; Lys05; or a pharmaceutically acceptable salt thereof.
  • an anticancer G4L may be 20A; quarfloxin; or a pharmaceutically acceptable salt thereof, and a lysosomotropic agent may be chloroquine; Lys05; or a pharmaceutically acceptable salt thereof.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a combination as disclosed herein and a pharmaceutically acceptable excipient or carrier.
  • the present invention relates to a kit-of-parts comprising at least a first and a second containers, the first container is containing a first composition comprising at least one anticancer G-quadruplex ligand according to the invention, and the second container is containing a second composition comprising at least one lysosomotropic agent according to the invention.
  • the invention relates to a combination according to the invention, or a pharmaceutical composition according to the invention, or a kit-of-parts according to the invention, for use in prevention and/or treatment of a cancer disease.
  • a combination or a pharmaceutical composition or a kit-of-parts according to the invention may be for use in a synergistic prevention and/or treatment of a cancer disease.
  • a combination or a pharmaceutical composition or a kit-of-parts according to the invention may be for use in prevention and/or treatment of a chemoresistant cancer disease.
  • the anticancer G4L and the lysosomotropic agent may be for simultaneous, separate or sequential use.
  • a combination or a pharmaceutical composition or kit-of-parts according to the invention may be for use in prevention and/or treatment of cancer disease selected from breast cancer; colon cancer; rectal cancer; endometrial cancer; gastric carcinoma (including gastrointestinal carcinoid tumors and gastrointestinal stromal tumors); glioblastoma; hepatocellular carcinoma; cervical carcinoma; lung adeno-carcinoma (including small cell lung cancer and non-small cell lung cancer (NSCLC)); melanoma, including uveal melanoma; medulloblastoma; ovarian carcinoma; osteosarcoma; pancreatic cancer; prostate cancer; acute myelogenous leukemia (AML); chronic myelogenous leukemia (CML); non- Hodgkin's lymphoma; thyroid carcinoma; and pediatric tumors, such as leukemia, brain tumors, nephroblastoma, neuroblastoma, lymphoma, embryonic tumors, and rhab
  • the invention also relates a method of synergistically preventing and/or treating a cancer disease in a subject in need thereof, said method includes administering to the subject a synergistically therapeutic effective amount of at least one anticancer G4L and at least one lysosomotropic agent, or a pharmaceutically acceptable salt thereof, thereby treating a cancer disease in said subject.
  • the method includes observing a prevention or a treatment, such as a relieving, of the cancer disease.
  • the invention also relates to a method of preventing and/or treating a cancer disease in a subject in need thereof, said method includes administering to the subject a therapeutically effective amount of at least one anticancer G4L and at least one lysosomotropic agent, or a pharmaceutically acceptable salt thereof, thereby treating a cancer disease in said subject.
  • the invention also relates to a method for the prevention and/or treatment of a chemoresistant and/or potentially chemoresistant cancer disease in a subject in need thereof, said method includes administering to the subject a therapeutic effective amount of at least one anticancer G4L and at least one lysosomotropic agent, or a pharmaceutically acceptable salt thereof, thereby treating a chemoresistant cancer disease in said subject.
  • the method includes observing a prevention or a treatment, such as a relieving, of the chemoresistant and/or potentially chemoresistant cancer disease.
  • the invention also relates to a method for the synergistic prevention and/or treatment of a chemoresistant and/or potentially chemoresistant cancer disease in a subject in need thereof, said method includes administering to the subject a synergistically therapeutic effective amount of at least one anticancer G4L and at least one lysosomotropic agent, or a pharmaceutically acceptable salt thereof, thereby treating a chemoresistant cancer disease in said subject.
  • the method includes observing a synergistic prevention or a synergistic treatment, such as a relieving, of the cancer disease.
  • Figure 1 shows that 20A and chloroquine act in concert to trigger cell death.
  • A) HeLa cells and A549 cells were treated with the indicated concentration of 20A with (CQ - grey bars) or without (control - black bars) 25mM of chloroquine for 24h.
  • Cell death was assessed by evaluating plasma membrane permeability using propidium iodide dye following flow cytometer analysis. The data represents the mean ⁇ SD of 6 values obtained from three independent experiments each performed in duplicate. ** p-value ⁇ 0.01 using Mann-Whitney test.
  • Figure 2 shows that 20A and chloroquine act in concert to trigger LMP in the cancer cells U20S expressing Galectin3-mCherry cells.
  • Data are presented as mean ⁇ SD of 15 values obtained from 5 randomly chosen fields in each of the three independent experiments.
  • Apoptotic cell death was assessed by immunoblot analysis of cleaved forms of either Caspase 3 or PARP1 . Actin-b was detected as a loading control.
  • Apoptotic cell death was assessed by measurement of loss of mitochondrial transmembrane potential (DYGTI). The data represents the mean ⁇ SD of 6 values obtained from three independent experiments each performed in duplicate. ** p-value ⁇ 0.01 using Mann-Whitney test.
  • Figure 4 shows that 20A and Lys05 (Ly05) act in concert to trigger cell death.
  • U20S cells were treated with the indicated concentration of 20A (0, 1 , 2, 3, 4 and 5 mM) with (Ly05 1 or 5 mM - respectively light or medium grey bars) or without (no Ly05 - black bars) Lys05 for 24h.
  • Cell death was assessed by evaluating plasma membrane permeability using DAPI dye staining following flow cytometer analysis. The data represents the mean ⁇ SD of 6 values obtained from three independent experiments each performed in duplicate. ** p-value ⁇ 0.01 using Mann-Whitney test.
  • Figure 5 shows that quarfloxin (CX) and Chloroquine (Chloro) act in concert to trigger cell death.
  • U20S cells were treated with the indicated concentration of quarfloxin (CX) (0, 0.5, 1 , and 2 mM) with (Chloro 20 mM or 25 mM - respectively light or medium grey bars) or without (No Chloro - black bars) Chloroquine for 24h.
  • Cell death was assessed by evaluating plasma membrane permeability using DAPI dye staining following flow cytometer analysis. The data represents the mean ⁇ SD of 6 values obtained from three independent experiments each performed in duplicate. ** p-value ⁇ 0.01 using Mann-Whitney test.
  • anticancer G- quadruplex ligand anticancer G4L
  • G-quadruplexes are non-canonical nucleic acids secondary structures that form within guanine-rich strands of regulatory genomic regions. G4s have been extensively described in the human genome and have been found as having implications for various pharmacological and biological events, including cancers. Ligands (or agent) interacting with G4s have attracted great attention as potential anticancer therapies.
  • ligand refers to a molecule able to reversibly bind to a targeted macromolecule such as a protein or a nucleic acid and having a functional role, such as structural stabilization, catalysis, enzyme activity modulation, or signal transmission.
  • an “anticancer agent”, and preferably an “anticancer G-quadruplex ligand” as used herein refers to a molecule used to treat cancer through prevention, destruction or inhibition of cancer cells or tissues. Anticancer agents may be selective for certain cancers or certain tissues.
  • An anticancer G4L suitable for the invention is able to bind and stabilize G- quadruplex structures, hereby inducing cancer cell death and then anticancer activity. Not all G4Ls have anticancer activity.
  • G4Ls with anticancer activity are known to the skilled person (Asamitsu et al., Molecules 2019; 254:429; Sengupta et al., Molecules 2019; 254:582 ; Shivalingam et al. Nat Commun 2015; 6: 8178; Smith et al., Org Biomol Chem. 2011 ; 9(17):6154-62; Li et al., Current Pharmaceutical Design 2012; 18, 1973-1983).
  • anticancer G4Ls that may be useful for the invention, one may mention the following compounds and their derivatives.
  • “derivative(s)” with respect to a particular compound or a particular family of compounds is intended to mean a compound or a set of compounds presenting substantially the same chemical structure for substantially the same biological or pharmacological activity.
  • a derivative of a compound or of a family of compound is a bioisostere.
  • a bioisostere is a structural analogue of a compound (parent compound) obtained by substitution of an atom or a group of atoms in the parent compound for another with similar electronic and steric characteristics and which retains the biological or pharmacological activity of the parent compound.
  • a chlorine -Cl group may be replaced by a trifluoromethyl -CF 3 group, or by a cyano -CoN group.
  • a phenyl -C 6 H 5 ring can be replaced by a different aromatic ring such as thiophene or naphthalene.
  • the chemical structure of a derivative according to the invention may differ from the chemical structure of a reference compound (i) by the absence of one or more substituents and/or (ii) the presence of one or more supplemental substituents and/or (iii) the substitution of one or more substituents by another having substantially the same physico-chemical properties, for instance a fluorine by a chlorine or a methyl by an ethyl, in such a manner that the derivative has substantially the same biological or pharmacological activity than the reference compound.
  • the term “substantially” used in conjunction with a feature of the disclosure intends to define a set of embodiments related to this feature which are largely but not wholly similar to this feature in such a manner that the difference does not materially affect the nature of the feature.
  • Triarylpyridines having an anticancer G4L activity such as the compounds described in Smith et al. ( Org Biomol Chem. 2011 ; 9(17):6154-6220A), in particular 20A (compound 3 in Smith et al.) which has been proposed against cervical carcinoma, lung adeno carcinoma, and osteosarcoma;
  • CX-5461 and CX-3543 have a specific toxicity against breast cancer cells. Furthermore, quarfloxin has completed Phase II trials as a candidate therapeutic agent against several tumors, including neuroendocrine tumors, carcinoid tumors, and lymphoma.
  • IZNP1 (2-(4-(4,5-bis(4-(4-methylpiperazin-1 -yl)phenyl)-1 H-imidazol-2-yl)phenyl)- 6-(4-methylpiperazin-1 -yl)-1 H-benzo[de]isoquinoline-1 ,3(2H)-dione), proposed against squamous cell carcinoma;
  • IZCZ-3 (9-ethyl-3-[1 -(4-methoxyphenyl)-4,5-bis[4-(4-methylpiperazin-1 - yl)phenyl]imidazol-2-yl]carbazole) proposed against squamous cell carcinoma, cervical cancer, liver cancer, malignant melanoma;
  • T3 ⁇ 4 1 proposed against colorectal carcinoma
  • NDI naphtalene diimides
  • telomestatin a macrocycle naturally occurring in Streptomyces annulatus ;
  • telomestatin derivative as disclosed in WO 2009/157505 A1
  • porphyrin and porphyrazine derivatives thereof such as N-methyl Meso Porphyrin IX (NMM) or TMPyP4, a cationic porphyrin proposed against mammary tumors and human prostate carcinomas;
  • a G-quadruplex ligand is not a metal-based complex. In another embodiment, a G-quadruplex ligand is not a ruthenium-based complex. As exemplary embodiment, it is not a polypyridyl chiral ruthenium (II) complex. In one embodiment, it is not a A-[Ru(phen) 2 (p-DMNP)] 2+ or a A-[Ru(phen) 2 (p-DMNP)] 2+ as described in Sun et al., J Inorg Biochem, 2015.
  • a combination as disclosed herein does not comprise, or does consist of, a combination of a ruthenium-based complex and of chloroquine.
  • a combination as disclosed herein does not comprise, or does consist of, a combination of A-[Ru(phen) 2 (p-DMNP)] 2+ or a A-[Ru(phen) 2 (p-DMNP)] 2+ and of chloroquine.
  • a combination as disclosed herein does not comprise, or does consist of, a combination of A-[Ru(phen) 2 (p-DMNP)] 2+ and of chloroquine.
  • pharmaceutically acceptable salts of an anticancer G4L may also be used.
  • a "pharmaceutically acceptable salt” of an agent in accordance with the invention means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent agent. It is understood that the pharmaceutically acceptable salts are non-toxic.
  • the term “salt” refers to acid or base salts of agents used in the present invention. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.
  • the neutral forms of the agents are preferably regenerated by contacting the salt with a base or acid and isolating the parent agent in the conventional manner.
  • the parent form of the agent differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • an anticancer G4L useful for the invention may be preferably selected in the group consisting in triarylpyridines; fluoroquinolones and derivatives thereof; acridine and acridinium derivatives; berberine and epiberberine; naphtalene diimides (NDI); quindoline; indoloquinolines; quinazolone derivatives; telomestatin; L1 H1 -70TD; cyanine derivatives; topotecan ; porphyrin and porphyrazine derivatives, such as N-methyl MesoPorphyrin IX (NMM) or TMPyP4; SYUIQ-FM05; pyridostatin; bisquinolinium derivatives such as 360A or PhenDC3; or a pharmaceutically acceptable salt thereof.
  • an anticancer G4L useful for the invention may be selected in the group consisting in triarylpyridines; fluoroquinolones; acridines; berberine and epiberberine; naphtalene diimides (NDI); quindoline; indoloquinolines; quinazolones; telomestatin; L1 H1-70TD; cyanines; topotecan ; porphyrin and porphyrazines, such as N- methyl MesoPorphyrin IX (NMM) or TMPyP4; SYUIQ-FM05; pyridostatin; bisquinoliniums, such as 360A or PhenDC3; or a pharmaceutically acceptable salt thereof.
  • an anticancer G4L useful for the invention may be preferably selected in the group consisting in triarylpyridines; fluoroquinolones and derivatives thereof; or a pharmaceutically acceptable salt thereof.
  • an anticancer G4L useful for the invention may be a triarylpyridine or a pharmaceutically acceptable salt thereof, and preferably may be the triarylpyridine 20A, or a pharmaceutically acceptable salt thereof, and more preferably is the triarylpyridine 20A.
  • triarylpyridine compounds suitable for the invention are described in the publication of Smith et al. Org Biomol Chem. 2011 ; 9(17):6154-62.
  • 20A is the triarylpyridine compound n°3 of the publication of Smith etal. Org Biomol Chem. 2011 ; 9(17):6154-62.
  • an anticancer G4L useful for the invention may be a fluoroquinolone, a derivative thereof, or a pharmaceutically acceptable salt thereof.
  • a fluoroquinolone suitable for the invention may be quarfloxin (CX-3543), or a pharmaceutically acceptable salt thereof, and preferably is quarfloxin.
  • a fluoroquinolone derivative suitable for the invention may be CX-5461 (pidnarulex), or a or a pharmaceutically acceptable salt thereof, and preferably is CX-5461 .
  • an anticancer G4L useful for the invention may be triarylpyridine 20A, quarfloxin or CX-5461 , or a or a pharmaceutically acceptable salt thereof, and preferably is triarylpyridine 20A or quarfloxin; or a pharmaceutically acceptable salt thereof, and preferably is triarylpyridine 20A or quarfloxin.
  • An anticancer G4L is used in a therapeutically effective amount.
  • an “effective amount” or a “therapeutically effective amount” as used herein is an amount sufficient for an agent or a combination of agents, as considered here, to contribute to the treatment or prevention of a cancer disease or of a symptom of a cancer disease.
  • the exact amounts will depend on the various factors, such as the purpose of the treatment, the age, weight, or sex of the patient, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
  • Effective amounts, or dosages may be varied depending upon the requirements of the patient and the anticancer G4L being employed.
  • the dose administered to a patient, in the context of the present invention should be sufficient to induce a beneficial cancer treatment or prevention in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner, and will vary depending on the compounds, the combinations, the disease state and its severity, the bioavailability characteristics of the compounds, the age of the patient to be treated, and the like.
  • a suitable therapeutically effective amount for an anticancer G4L in accordance with the invention may be, for example, within the range of 5 to 25, preferably 10 to 20, more preferably about 15 mg/kg. This dosage may be particularly useful for triarylpyridine 20A or for fluoroquinolone quarfloxin.
  • an anticancer G4L in accordance with the invention can be administered for several days, weeks or months, and for example for 2 weeks, or more preferably for one week.
  • an anticancer G4L in accordance with the invention maybe administered for 5 consecutive days over 7 days, for two weeks.
  • Lysosomotropic agent are compounds, lipophilic or amphiphilic with a basic moiety, able to be protonated and trapped within lysosomes (Giralod et al., Biochem Soc Trans, 2014; Kuzu eta!., Pharmacological Research, 2017).
  • Lysosomes are advanced organelles involved in many cellular processes and are considered crucial regulators of cell homoeostasis.
  • the interior is acidic with a pH of ⁇ 5 and contains over 50 hydrolases, able to degrade all constituents of the cell.
  • Lysosomes are limited by a single 7-10-nm phospholipid bilayer that functions as an interface to regulate communication between the lysosomal lumen and the cytosol. Owing to their high hydrolase content, leakage of lysosomal content to the cytosol is potentially harmful to the cell. Partial permeabilization of the membrane induces apoptosis, whereas massive lysosomal rupture induces necrosis.
  • Lysosomal membrane permeabilization LMP is characterized as any damage to the lysosomal membrane that results in the release of the lysosomal contents into the cytosol
  • a lysosomotropic agent suitable for the invention is a compound able to relocate all or part of the lysosomal content to the cytosol.
  • a lysosomotropic agent suitable for the invention is an active agent which accumulate inside acidic compartments.
  • lysosomotropic agent suitable for the invention, one may mention the imaging method described by Nadanaciva et al. (Toxicology in Vitro. 2011 , 25(3), 715-723) or by Seo et al., ( Biochemical and Biophysical Research Communications, 2014, 450(1), 189-194).
  • lysosomotropic agents that may be useful for the invention, one may mention:
  • Chloroquine has already been proposed for the treatment of some cancer diseases;
  • pharmaceutically acceptable salts of a lysosomotropic agent may also be used.
  • a "pharmaceutically acceptable salt” has the definition as previously provided.
  • a lysosomotropic agent may be chloroquine; oxychloroquine; hydroxychloroquine; Lys05; siramesine; GNS561 ; or a pharmaceutically acceptable salt thereof.
  • a lysosomotropic agent may be chloroquine; oxychloroquine; hydroxychloroquine; or a pharmaceutically acceptable salt thereof.
  • a lysosomotropic agent may be chloroquine or a pharmaceutically acceptable salt thereof, and preferably is chloroquine diphosphate.
  • a lysosomotropic agent may be Lys05 or a pharmaceutically acceptable salt thereof, and preferably is Lys05.
  • a lysosomotropic agent may be selected among the group consisting in chloroquine; chloroquine diphosphate; hydroxychloroquine, and Lys05.
  • a lysosomotropic agent may be selected among the group consisting in chloroquine; Lys05; and a pharmaceutically acceptable salt thereof.
  • a lysosomotropic agent may be selected among the group consisting in chloroquine diphosphate and Lys05.
  • a lysosomal membrane permeabilization inducing agent is used in a therapeutically effective amount. “Effective amount” or a “therapeutically effective amount” have the definition as previously provided. Dosages may be varied depending upon the requirements of the patient and the lysosomal membrane permeabilization inducing agents being employed.
  • a lysosomotropic agent such as chloroquine or hydroxychloroquine, or a pharmaceutically acceptable thereof, may be administered at a therapeutically effective amount ranging from 10 to 1000 mg/per dose, from 20 to 800 mg/dose, from 50 to 400 mg/dose, from 100 to 300 mg/dose.
  • a dosage useful for chloroquine may be in a range from 100 to 1000 mg/dose, from 150 to 800 mg/dose, or from 200 to 500 mg/dose.
  • the present invention is directed to a combination comprising at least one anticancer G4L and at least one lysosomotropic agent, or a pharmaceutically acceptable salt thereof.
  • a combination envisages the simultaneous, sequential or separate administration of the components of the combination.
  • a combination envisages simultaneous administration of the anticancer G4L and the lysosomotropic agent.
  • a combination envisages sequential administration of those agents.
  • a combination envisages separate administration of those agents. Where the administration of those agents is sequential or separate, the delay in administering the second component should not be such as to lose the benefit of the effect of the combination therapy, in particular the synergistic effect.
  • the combination according to the invention comprises therapeutically active amount of the active agents. Accordingly, a combination in accordance with the invention is therapeutically active.
  • a combination according to the invention is able to induce lysosomal membrane permeabilization or LMP, and to trigger cancer cells death.
  • the active agents of the combination of the invention an anticancer G4L and a lysosomotropic agent, are able to synergistically induce LMP and to synergistically trigger cancer cells death.
  • the active agents of a combination of the invention may not induce LMP when used alone. However, when they are used in a combination of the invention, the resulting combination may induce LMP and may trigger cancer cells death.
  • LMP can be measured by a variety of simple techniques. Immunofluorescence techniques using antibodies against cathepsins such as CB and CD can reveal the redistribution of these proteases from lysosomes to the cytosol.
  • cathepsins lysosomal enzymes
  • lysosomal enzymes such as cathepsins. These proteins can be visualized by fluorescence microscopy. Cathepsins confined within intact lysosomes are visualized as a punctate pattern of intense fluorescence and can be co-stained with antibodies against LAMP-1 or LAMP-2. By contrast, cathepsins released during LMP produce a diffuse fluorescence pattern throughout the cell. Cytosolic release of cathepsins can also be detected by Western blot of the cytosolic fractions after cell fractionation. This method can be used to estimate the extent of LMP by simultaneously determining the levels of several cathepsins of different sizes over time.
  • cathepsins in cytosolic extracts can be detected using cathepsin-specific substrates (eg, Magic Red) and a fluorescence plate reader. Fluorescence microscopy can also be used to count cathepsin-positive cells in tissue sections. Those methods, and others, are well-known to the skilled person.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a combination comprising at least one anticancer G4L and at least one lysosomotropic agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • the invention is directed to a kit-of-parts comprising at least a first and a second containers, said first container containing a first composition comprising at least one anticancer G4L, and said second container containing a second composition comprising at least one lysosomotropic agent.
  • compositions of the kit-of-parts are pharmaceutical compositions.
  • the anticancer G4L and lysosomotropic agent are as defined herein.
  • the anticancer G4L is as defined herein 20A or quarfloxin.
  • the lysosomotropic agent is as defined herein chloroquine, or a pharmaceutically acceptable salt thereof, such as chloroquine diphosphate, or is Lys05.
  • compositions or combinations provided herein comprise the active agents in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose.
  • a therapeutically effective amount i.e., in an amount effective to achieve its intended purpose.
  • the actual effective amount for a particular application will depend, inter alia, on the condition being treated and various other factors well-known in the art such as the age, the weight, the sex of the patient, the presence of other potential aggravating conditions, or the diet. Determination of a therapeutically effective amount of a compound of the invention is well within the capabilities of those skilled in the art.
  • compositions or combinations described herein can be prepared according to techniques known to the skilled person by using a combination of at least one anticancer G4L and at least one lysosomotropic agent, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier.
  • compositions may comprise one or more pharmaceutically acceptable excipients or carriers.
  • suitable carriers and excipients and their formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Edition, David B. Troy, ed., Lippicott Williams & Wilkins (2005).
  • pharmaceutically acceptable carrier is meant a material that is not biologically or otherwise undesirable, i.e., the material is administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with the other components of the pharmaceutical composition in which it is contained.
  • compositions can be in any form deemed appropriate by the skilled person, such as solid, semi-solid, liquid, granular, inhalation or aerosol inhalation.
  • the liquid forms may be appropriate forms for oral or systemic administration.
  • compositions suitable for oral administration can be capsules, tablets, pills, powders, granules, solutions or suspensions in aqueous or non-aqueous liquids, foam or beaten edible, liquid oil in water emulsions or liquid water in oil emulsions.
  • the active agents mentioned herein may be combined with pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and similar.
  • pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and similar.
  • flavourings, preservative, colouring coating and/or dispersant agents may also be present.
  • compositions suitable for parenteral administration may include sterile aqueous or non-aqueous solution for injection which may contain antioxidants, buffers, bacteriostatic and solutes which render the solution isotonic with the blood of the intended recipient, and aqueous or non-aqueous sterile suspensions which may include suspending and thickening agents. These compositions may be sterilized by conventional, well known sterilization techniques.
  • a parenteral composition may include a solution or suspension of the compounds in a vehicle such as sterile water or a parenterally acceptable oil. Alternatively, the solution can be lyophilized. The lyophilized parenteral pharmaceutical composition can be reconstituted with a suitable solvent just prior to administration.
  • compositions may be presented in single dose or multi-dose containers, for example, sealed ampoules or vials, and may be stored in lyophilized condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • sterile liquid carrier for example water for injections
  • Extemporaneous injection solutions and suspensions may be prepared from powders, granules, lyophilized and sterile compresses.
  • the composition may also be provided with the active ingredients in separate containers that can be suitably admixed according to the desired dosage taking into account the weight, age, gender and health status of the patient in need thereof.
  • the anticancer G4L and the lysosomotropic agent, or a pharmaceutically acceptable salt thereof may also be presented in separate compositions, packaged in separate containers, as a kit-of parts.
  • the separate compositions may then be admixed before administration for a simultaneous administration, or they may be administered separately or sequentially.
  • Cancer diseases, Therapeutic uses & Methods of treatment may also be presented in separate compositions, packaged in separate containers, as a kit-of parts.
  • the separate compositions may then be admixed before administration for a simultaneous administration, or they may be administered separately or sequentially.
  • the combination or the pharmaceutical composition or a kit-of- parts according to the invention are for use in prevention and/or treatment of a cancer disease.
  • the invention relates to the use of a combination according to the invention for the manufacture of a medicament for the prevention and/or treatment of a cancer disease.
  • the invention relates to the use of a combination according to the invention for the manufacture of a kit-of-parts for the prevention and/or treatment of a cancer disease, preferably a chemoresistant cancer disease.
  • Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more cancer symptoms or conditions, diminishment or reduction of the extent of a cancer disease or of a cancer symptom, stabilizing, i.e., not worsening, the state of a cancer disease or of a cancer symptom, prevention of a cancer disease or of a cancer symptom’s spread, delay or slowing of cancer disease or cancer symptom progression, amelioration or palliation of the cancer disease state, diminishment of the reoccurrence of cancer disease, and remission, whether partial or total and whether detectable or undetectable.
  • treatment as used herein includes any cure, amelioration, or reduction of a cancer disease or symptom.
  • a “reduction” of a symptom or a disease means decreasing of the severity or frequency of the disease or symptom, or elimination of the disease or symptom.
  • Prevent refers to a decrease in the risk of occurrence of a cancer disease or symptom in a patient. As indicated above, the prevention may be complete, i.e. no detectable symptoms or disease, or partial, such that fewer symptoms or less severity of the disease are observed than would likely occur absent treatment.
  • the combination or the pharmaceutical composition or the kit-of-parts according to the invention are for use in synergistic prevention and/or treatment of a cancer disease.
  • the combination or the pharmaceutical composition or the kit-of-parts according to the invention are for use in prevention and/or treatment of a chemoresistant cancer disease.
  • the combination or the pharmaceutical composition or the kit-of-parts according to the invention are for use in a synergistic prevention and/or treatment of a chemoresistant cancer disease.
  • the manufactured medicament or kit-of-parts described herein are for a synergistic prevention and/or synergistic treatment of a cancer disease, preferably a chemoresistant cancer disease.
  • “synergy” or “therapeutic synergy” are used when the combination of two products at given doses is more efficacious than the best of the two products alone considering the same doses.
  • each of the active agent i.e. the anticancer G4L and the lysosomotropic agent, composing the combination may be present in an amount below their usual prescribed effective amount or therapeutically effective amount as active agent.
  • the anticancer G-quadruplex ligand and the lysosomal membrane permeabilization inducing agent may be each present in a combination according to the invention in a synergistic amount.
  • a synergistic amount is, with respect to a given active agent, a fraction of the usually prescribed effective amount or therapeutically effective amount.
  • a "usually prescribed effective amount or therapeutically effective amount of an active agent” refers to the amount or dose of a therapeutic agent typically used as a unit dose in the standard medical protocols or indicated in the accompanying documentation of the packages of the therapeutic agents known to the skilled person. This value, recognizable by the skilled person, varies from drug to drug and cannot be defined in a way applicable to all the commonly used therapeutic agents. The definition, applied to any active agent, indicates exactly the dosage commonly prescribed and specified in the medical and pharmacological protocols for therapy for each active agent known to the skilled person. In one embodiment, a synergistically therapeutic efficient amount of the anticancer
  • G4L may be about 0.1 , 1.0, 2.0, 5.0, 10.0, 15.0, 20.0, 30.0, 40.0, 50.0, 70.0, 80.0, 90.0, 95.0, or 99.0% of the therapeutically efficient amount of the anticancer G4L provided herein when used separately from the lysosomotropic agent.
  • a synergistically therapeutic efficient amount of the lysosomotropic agent may be about 0.1 , 1.0, 2.0, 5.0, 10.0, 15.0, 20.0, 30.0, 40.0, 50.0, 70.0, 80.0, 90.0, 95.0, or 99.0% of the therapeutically efficient amount of the lysosomotropic agent provided herein when used separately from the anticancer G4L.
  • a combination or a pharmaceutical composition or a kit-of- parts according to the invention comprises at least one anticancer G4L in a synergistically therapeutic efficient amount and at least one lysosomotropic agent in a synergistically therapeutic efficient amount.
  • the invention also relates to a method of preventing and/or treating a cancer disease in a subject in need thereof, said method includes administering to the subject a therapeutically effective amount of at least one anticancer G4L and at least one lysosomotropic agent, or a pharmaceutically acceptable salt thereof, thereby treating a cancer disease in said subject.
  • “Patient” or “subject in need thereof” as used herein refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a composition according to the invention.
  • Non-limiting examples include mammals: human, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, or non-mammalian animals.
  • a subject or a patient is a mammal, and preferably is human.
  • the invention also relates a method of synergistically preventing and/or treating a cancer disease in a subject in need thereof, said method includes administering to the subject a synergistically therapeutic effective amount of at least one anticancer G4L and at least one lysosomotropic agent, or a pharmaceutically acceptable salt thereof, thereby treating a cancer disease in said subject.
  • the method includes observing a prevention or a treatment, such as a relieving, of the cancer disease.
  • the invention also relates to a method for the prevention and/or treatment of a chemoresistant and/or potentially chemoresistant cancer disease in a subject in need thereof, said method includes administering to the subject a therapeutic effective amount of at least one anticancer G4L and at least one lysosomotropic agent, or a pharmaceutically acceptable salt thereof, thereby treating a chemoresistant cancer disease in said subject.
  • the method includes observing a prevention or a treatment, such as a relieving, of the chemoresistant and/or potentially chemoresistant cancer disease.
  • the invention also relates to a method for the synergistic prevention and/or treatment of a chemoresistant and/or potentially chemoresistant cancer disease in a subject in need thereof, said method includes administering to the subject a synergistically therapeutic effective amount of at least one anticancer G4L and at least one lysosomotropic agent, or a pharmaceutically acceptable salt thereof, thereby treating a chemoresistant cancer disease in said subject.
  • the method includes observing a synergistic prevention or a synergistic treatment, such as a relieving, of the cancer disease.
  • the at least one anticancer G4L and at least one lysosomotropic agent, or pharmaceutically acceptable salts thereof are administered as a combination. In embodiments, in the methods described herein, the at least one anticancer G4L and at least one lysosomotropic agent, or pharmaceutically acceptable salts thereof, are administered as a pharmaceutical composition.
  • the invention is directed to a combination or a pharmaceutical composition or a kit-of-parts or a method employing such combination, pharmaceutical composition, or a kit-of-parts, as described here, wherein the anticancer G4L and the lysosomotropic agent are for simultaneous, separate or sequential use.
  • the anticancer G4L and the lysosomotropic agent may be administered in combination either simultaneously (e.g ., as a mixture), separately but simultaneously (e.g., via separate intravenous lines) or sequentially (e.g., one agent is administered first followed by administration of the second agent).
  • combination is used to refer to concomitant, simultaneous or sequential administration of the anticancer G4L and the lysosomotropic agent.
  • administering means administration by any route, such as oral administration, administration as a suppository, topical contact, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, subcutaneous or transmucosal (e.g ., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal) administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject, including parenteral.
  • Parenteral administration includes intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Administration can include delivery to a patient of the active agents, e.g. an anticancer G4L and a lysosomotropic agent, simultaneously in the form of a single entity or dosage.
  • Administration can also include that the active agents are both administered to a patient as separate entities either simultaneously, concurrently, or sequentially with no specific time limits, such that the administration provides therapeutically effective levels of the combination of active agents in the body of the patient.
  • the anticancer G4L and the lysosomotropic agent are administered simultaneously or separately.
  • the anticancer G4L and the lysosomotropic agent are administered sequentially.
  • the G4L and the lysosomotropic agent may at times be administered sequentially and at other times be administered simultaneously or separately.
  • the anticancer G4L and the lysosomotropic agent are administered sequentially, the anticancer G4L is administered at a first time point and the lysosomotropic agent is administered at a second time point, wherein the first time point precedes the second time point.
  • the lysosomotropic agent is administered at a first time point and the anticancer G4L is administered at a second time point, wherein the first time point precedes the second time point.
  • the active agents are admixed prior to administration.
  • uses or methods in accordance with the invention preferably implement 20A or quarfloxin as the anticancer G4L, and chloroquine or Lys05, as the lysosomotropic agent, or a pharmaceutically acceptable salt thereof.
  • the course of a treatment with a combination of the invention is best determined on an individual basis, depending on the particular characteristics of the subject and the type of treatment selected.
  • the treatment such as those disclosed herein, can be administered to the subject on a daily, twice daily, bi-weekly, monthly or any applicable basis that is therapeutically effective.
  • the treatment can be administered alone or in association with any other treatment disclosed herein or known in the art.
  • the additional treatment can be administered simultaneously with the first treatment, at a different time, or on an entirely different therapeutic schedule ( e.g ., the first treatment can be daily, while the additional treatment is weekly).
  • the combination or the pharmaceutical composition as described herein can be administered simultaneously, separately, or sequentially, daily for a period of time extending from at least one day up to several days, for instance up to 30 days, or several months, for instance up to 3 months.
  • the administration may be repeated for several period of times separated by a period of time without administration. For instance, the administration may be carried out over two period of one month separated by a period of one month without administration. Such sequence may be repeated at least once or several times.
  • the combination or the pharmaceutical composition as described herein can be administered once, twice, three time or 4 time a day, or once a day over a period of time ranging from a few minutes, e.g. one minutes, up to several minutes, e.g. 40, 50 or 60 minutes or up to several hours, one, two, three or up to 6 or 8 hours.
  • the exact dosage, frequency and length of administration will depend on the particular combination of anticancer G4L and lysosomotropic agent used, the particular condition to be treated, the severity of the condition to be treated, age, weight and the overall physical condition of the particular patient as well as on other medications that the patient is taking, as is well known to experts in the field.
  • a cancer in particular a chemoresistant cancer, which may be considered within the invention may be selected from breast cancer; colon cancer; rectal cancer; endometrial cancer; gastric carcinoma (including gastrointestinal carcinoid tumors and gastrointestinal stromal tumors); glioblastoma; hepatocellular carcinoma; cervical carcinoma; lung adeno carcinoma (including small cell lung cancer and non-small cell lung cancer (NSCLC)); melanoma, including uveal melanoma; medulloblastoma; ovarian carcinoma; osteosarcoma; pancreatic cancer; prostate cancer; acute myelogenous leukemia (AML); chronic myelogenous leukemia (CML); non-Hodgkin's lymphoma; thyroid carcinoma; and pediatric tumors, such as leukemia
  • AML acute myelogenous leukemia
  • CML chronic myelogenous leukemia
  • non-Hodgkin's lymphoma thyroid carcinoma
  • pediatric tumors such as leukemia
  • the cancer in particular the lung adeno-carcinoma, the cervical cancer or the osteosarcoma, may be a chemoresistant cancer.
  • the term “chemoresistance” or “chemoresistant cancer” refers to a reduction or a lack of responsivity of a cancer cell to a particular anticancer agent, used alone or in combination with other drugs commonly used in anticancer therapies. More particularly, a chemoresistant tumor or a chemoresistant cancer refers to a cancer that does not undergo cell death in response to a chemotherapeutic or anticancer agent.
  • composition effective in the treatment of chemoresistant and/or potentially chemoresistant cancer means composition which have the effect of inhibiting from the beginning the development of chemoresistant cells or to revert chemoresistance of cells treated with these substances and to restore the apoptotic pathway.
  • a combination of the invention is a such composition.
  • the human cervical cancer cell line HeLa was purchased from the American Type Culture Collection (ATCC) and the human lung carcinoma A549 cell line is a generous gift of Prof. Jean-Frangois Riou.
  • the autophagy-deficient (ATG5 and ATG7 depleted) HeLa cell lines were generated as described by O’Prey et at. (Methods Enzymol 2017; 588: 79-108).
  • the U20S Galectin3-mCherry cell line was as described in Montespan etal. (PLoS Pathog 2017; 13: e1006217) or in Martinez etal. (Methods Mol Biol. 2013; 1064: 211-226).
  • U20S cell lines are cultivated in DMEM, supplemented with 10% fetal bovine serum, 100 units/ml penicillin, and 100 pg/ml streptomycin (Gibco-Life technologies, 1540-122).
  • the lung adenocarcinoma PDX cell lines (PDX2) and (PDX3) are generous gifts from Dr. D. Santamaria (Ambrogio etal., Nat /We 2016; 22: 270-277).
  • HeLa cells were grown in RPMI 1640 culture media supplemented with 2 mM glutamine (Gibco-Life technologies), 10% fetal bovine serum (Gibco-Life technologies), 100 units/ml penicillin, and 100 pg/ml streptomycin (Gibco-Life technologies, 1540-122), while A549, U20S and PDX cell lines were grown in DMEM, supplemented with 10% fetal bovine serum, 100 units/ml penicillin, and 100 pg/ml streptomycin (Gibco-Life technologies, 1540- 122).
  • Antibodies against the following proteins were used: Cleaved-Caspase3 (#9664), LAMP-I (#9091) from Cell Signaling Technology, PARP-1 (C-2-10) (#BML-SA249-0050) from Enzo life sciences, b-Actin (#NB600-501) from Novus Biologicals, HRP conjugated rabbit (#111 -035-003) and HRP conjugated mouse (#115-035-174) from Jackson ImmunoResearch, Alexa488 conjugated anti-rabbit (#A11008) from Invitrogen.
  • the Hoechst 33258 (#14530), Propidium iodide (#P4864), Chloroquine diphosphate salt (#C6628), QVD-OPH (#SML0063) were purchased from Sigma-Aldrich. Tetramethylrhodamine methyl-ester, TMRM (T-668) was purchased from Molecular Probes, Fluoromount G (#00-4958-02) was purchased from Invitrogen. 20A was synthesized as previously described (Smith et a!., Org Biomol Chem. 2011 ; 9(17):6154-62 - compound n °3). Quarfloxin, a fluoroquinolone derivative with antineoplastic activity (also know as CX-3543), was obtained from Selleckchem. Lys05 was obtained from Sigma (Ref: SML2097).
  • Mitochondrial and lysosomal staining and evaluation of 20A localization Cells were grown on glass coverslips on a 6-well plate (6 c 10 4 cells/well), treated with or without 5 mM 20A for 6h. Cell were stained with 50nM Mitotracker Green (#M7514, Molecular probes) and 50nM Lysotracker Red DN-99 (#L7528, Molecular probes) 30 min before the end of the incubation time of 20A. Cells were placed in a perfusion chamber with DMEM without red Phenol containing 15nM Lysotracker Red DN-99. Image acquisition was made on a Zeiss LSM 510 METAconfocal microscope, with an Apoplan x63 objective. Identical exposures were used for each channel throughout individual experiments, and no images were altered after capture. Co-localization of blue fluorescence (20A) with the lysosome cellular compartment was analyzed by superposing fluorescence profile of the different cellular compartments.
  • Plasma membrane permeability is scored after labeling cells with specific fluorescent probes (propidium iodide (P4864, Sigma) ( Figure 1) or Hoechst 33342 (B2261 , Sigma) uptake ( Figures 4 and 5). Briefly, supernatant and attached cells were collected, pelleted at 1800rpm for 5min and loaded with either 1 pg/ml PI or Hoechst 33345 (10 mrLhI) during 15 min at room temperature. Cells were then analyzed by flow cytometer (FACSCalibur, Becton Dickinson) and the FlowJo software v10.
  • Apoptotic cell death was also determined by measuring the loss of mitochondrial transmembrane potential (DYGP) by using tetramethyl rhodamin methyl ester perchlorate dye (TMRM). Briefly, supernatant and attached cells were collected, pelleted at 1800rpm for 5min and loaded with 200nM TMRM for 30min at 37 °C in PBS supplemented with 20mM verapamil. Cells were then analyzed by flow cytometer (FACSCalibur, Becton Dickinson). Apoptosis was also evaluated by Western blotting analyses of cleaved forms of either PARP 1 or caspase 3. Where indicated, the caspase inhibitor, QVD- OPH (Sigma, SML0063) was added to cells to evaluate the possible implication of caspases in cell demise.
  • TMRM tetramethyl rhodamin methyl ester perchlorate dye
  • Lysosomal membrane damage was assessed thanks to U20S expressing Galectin3-mCherry cells.
  • Cells were plated on 12-well plates (7.5 c 10 4 cells/well) treated with or without 20A in either the presence or absence of 25mM chloroquine for 24h. Cells were then washed with PBS, fixed with 4% (v/v) paraformaldehyde for 10 min at room temperature and then nuclei were counterstained for 15 min with Hoechst 33258.
  • Image acquisition was made with a Leica DMI8 epifluorescence microscope, with a x20 objective (NA 0.40) equipped with a digital CMOS camera (Hamamatsu photonics) and filter bloc for detection of phase contrast and blue (exc: 325-375nm / em: 435-485nm) and red (exc: 541 -551 nm / em: 565-605nm) fluorescence. Each images of cells was collected with identical exposure times and scaled equally.
  • LMP lysosomal membrane permeabilization
  • proteins were transferred to a nitrocellulose membrane (10600003 Amersham Protrant Premium 0.45 NC, GE Healthcare Life Sciences). Protein loading was assessed by Ponceau red staining of membranes. Blots were then incubated with primary antibodies using the manufacturer's protocol followed by the appropriate horseradish peroxidase-conjugated secondary antibody. Mouse anti-Actin antibody was used to assess equal loading of the samples. Immunostained proteins were visualized on a chemiluminescence detector equipped with a camera (FUSION FX7, Fisher Bioblock Scientific) using the enhanced chemiluminescence (ECL) detection system. Statistical analysis.
  • Example II 20A accumulates at the lysosomal compartment and causes enlargement of the lysosomes
  • Example III 20A and chloroquine act in concert to trigger LMP and cell death.
  • the autophagy-deficient cells in which the formation of autophagosome is completely inhibited
  • U20S cells expressing Galectin3-mcherry were treated or not with 3 mM 20A either in the presence or absence of 25mM chloroquine for 24h and then immunostained for LAMP1 .
  • the obtained image data, obtained by z-projection of merge confocal images of nuclei (blue signal) and LAMP1 (green signal) revealed that 20A and chloroquine both causes the lysosomal enlargement as evidenced by Lamp1 staining but more interestingly is that this phenotype is markedly increased when the two drugs are combined.
  • the percentage of Gal3 positive cells is nearly equal in cells subjected to a sublethal dose of 20A and untreated cells (respectively 3% and 2%) but increases to 8 % when cells are exposed to chloroquine. More importantly, the percentage of Gal3 positive cells increased massively (39%) when chloroquine was associated with 20A treatment. It is worth noting that under the latter condition, 26% of Gal3 positive cells harbor one or two Gal3 puncta and the rest (13%) displays either 3 or more Gal3 punctae (Figure 2B) suggesting the presence of several endo-lysosomal membrane damages under this condition.
  • Example IV Apoptosis is involved in cell death induced by chloroquine/20A
  • Example V Combined treatment with chloroquine and 20A significantly activates cell death in patient-derived xenograft cell lines
  • lung cancer A549, PDX2 and PDX3
  • A549 lung cancer cell lines and two PDX from lung cancer PDX2 and PDX3 were treated with 3.5 mM 20A, in either the presence or absence of 25 mM chloroquine for 24h.
  • Cell death was assessed by scoring the percentage of propidium iodide positive cells by flow cytometer analysis. The obtained results showed that both PDX cell lines are highly sensitive to the combination treatment, suggesting the relevance of this combination for further studies in in vivo lung cancer models.
  • Example VI 20A combined with Lys05 significantly activates cell death
  • Lys05 is a dimeric chloroquine which accumulates in the lysosome and blocks autophagy (Amaravadi R.K, Winkler J.D., Autophagy. 2012 Sep 1 ; 8(9): 1383-1384).
  • Lys05 (Ly05: 0, 1 mM or 5 mM) with increasing amount of 20A (0, 1 mM, 2 mM, 3 mM, 4 mM and 5 mM) promoted a robust activation of cell death process (up to 80% cell death) in U20S cells as compared to 20A or Lys05 alone (less than 10% cell death).
  • Lys05 a lysosomotropic agent
  • 20A anticancer G4L
  • Quarfloxin is a fluoroquinolone derivative with antineoplastic activity which has been evaluated in clinical trial (Fitch T.R., Northfelt D.W., Griffin P.P., Goldston M., Lim J.K., Padgett C.S., Von Hoff D.D., Papadopoulos K.P. Journal of Clinical Oncology 26, no. 15, suppl (May 20, 2008) 14667-14667).

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  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le domaine de l'oncologie, et en particulier des maladies cancéreuses chimiorésistantes ou potentiellement chimiorésistantes. L'invention concerne une combinaison comprenant au moins un ligand G-quadruplexe anticancéreux (ligand G4), tel que la triarylpyridine 20A ou la quarfloxine, et au moins un agent lysosomotrope, tel que la chloroquine ou Lys05. De telles combinaisons favorisent une induction significative de la perméabilisation de la membrane lysosomale (LMP) par rapport à un seul traitement médicamenteux et déclenchent la mort cellulaire cancéreuse massive. L'effet synergique observé présente une application avantageuse dans la prévention et/ou le traitement du cancer chimiorésistant.
PCT/IB2020/000777 2019-11-29 2020-09-10 Compositions et leurs utilisations pour le traitement de cancers WO2021105761A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113387934A (zh) * 2021-06-07 2021-09-14 中山大学 一种多芳基取代咪唑衍生物及其制备方法与应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002013826A1 (fr) * 2000-08-02 2002-02-21 Keum Ki Chang Composition anticancereuse constituee de medicaments anticancereux et de medicaments antipaludiques
WO2009157505A1 (fr) 2008-06-25 2009-12-30 国立大学法人東京農工大学 Inhibiteur de la télomérase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002013826A1 (fr) * 2000-08-02 2002-02-21 Keum Ki Chang Composition anticancereuse constituee de medicaments anticancereux et de medicaments antipaludiques
WO2009157505A1 (fr) 2008-06-25 2009-12-30 国立大学法人東京農工大学 Inhibiteur de la télomérase

Non-Patent Citations (58)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2005, LIPPINCOTT, WILLIAMS & WILKINS
AITS ET AL., AUTOPHAGY, vol. 11, 2015, pages 1408 - 1424
AITS SKRICKER JLIU BELLEGAARD A-MHAMALISTO STVINGSHOLM S ET AL.: "Sensitive detection of lysosomal membrane permeabilization by lysosomal galectin puncta assay", AUTOPHAGY, vol. 11, 2015, pages 1408 - 1424
AMARAVADI R.KWINKLER J.D., AUTOPHAGY, vol. 8, no. 9, 1 September 2012 (2012-09-01), pages 1383 - 1384
AMARAVADI R.KWINKLER J.D.: "Lys05 - A new lysosomal autophagy inhibitor", AUTOPHAGY, vol. 8, no. 9, 1 September 2012 (2012-09-01), pages 1383 - 1384
AMBROGIO CGOMEZ-LOPEZ GFALCONE MVIDAL ANADAL ECROSETTO N ET AL.: "Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma", NAT MED, vol. 22, 2016, pages 270 - 277
AMBROGIO ET AL., NAT MED, vol. 22, 2016, pages 270 - 277
ASAMITSU SOBATA SYU ZBANDO TSUGIYAMA H: "Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy", MOLECULES, vol. 254, 2019, pages 429
BRUN, S.BASSISSI, F.SERDJEBI, C. ET AL.: "GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma", INVEST NEW DRUGS, vol. 37, 2019, pages 1135 - 1145, XP036942091, Retrieved from the Internet <URL:https://doi.org/10.1007/s10637-019-00741-3> DOI: 10.1007/s10637-019-00741-3
CAS , no. 9048-46-8
CHUN-PING DONG ET AL: "4,6-Dihydroxysalicylic Acid-Catalyzed Oxidative Condensation of Benzylic Amines and Aromatic Ketones for the Preparation of 2,4,6-Trisubstituted Pyridines and Its Application to Metal-Free Synthesis of G-Quadruplex Binding Ligands", ACS OMEGA, vol. 4, no. 5, 23 May 2019 (2019-05-23), pages 9029 - 9040, XP055717032, ISSN: 2470-1343, DOI: 10.1021/acsomega.9b00999 *
DUTTA DDEBNATH MMULLER D ET AL.: "Cell penetrating thiazole peptides inhibit c-MYC expression via site-specific targeting of c-MYC G-quadruplex", NUCLEIC ACIDS RES., vol. 46, no. 11, 2018, pages 5355 - 5365
FITCH T.R.NORTHFELT D.W.GRIFFIN P.P.GOLDSTON M.LIM J.K.PADGETT C.S.VON HOFF D.DPAPADOPOULOS K.P.: "Phase I clinical trial of quarfloxin administered weeklyx3 of a four week cycle", JOURNAL OF CLINICAL ONCOLOGY, vol. 26, 20 May 2008 (2008-05-20), pages 14667 - 14667
GIRALDO A.V.M.APPELQVIST H.EDERTH T.OLLINGER K.: "Lysosomotropic agents: impact on lysosomal membrane permeabilization and cell death", BIOCHEM. SOC. TRANS., vol. 42, 2014, pages 1460 - 1464
GIRALOD ET AL., BIOCHEM SOC TRANS, 2014
GOLDMAN ET AL., BIOANALYSIS, vol. 1, 2009, pages 1445 - 1459
GOLDMAN SDBFUNK RSRAJEWSKI RAKRISE JP: "Mechanisms of amine accumulation in, and egress from, lysosomes", BIOANALYSIS, vol. 1, 2009, pages 1445 - 1459, XP055598809, DOI: 10.4155/bio.09.128
GONG YDUVVURI MDUNCAN MBLIU JKRISE JP: "Niemann-Pick C1 protein facilitates the efflux of the anticancer drug daunorubicin from cells according to a novel vesicle-mediated pathway", J PHARMACOL EXP THER, vol. 316, 2006, pages 242 - 247
HERLEVSEN MOXFORD GOWENS CRCONAWAY MTHEODORESCU D: "Depletion of major vault protein increases doxorubicin sensitivity and nuclear accumulation and disrupts its sequestration in lysosomes", MOL CANCER THER, vol. 6, 2007, pages 1804 - 1813
HOMEWOOD CAWARHURST DCPETERS WBAGGALEY VC: "Lysosomes, pH and the Anti-malarial Action of Chloroquine", NATURE, vol. 235, 1972, pages 50 - 52
HOMEWOOD ET AL., NATURE, vol. 235, 1972, pages 50 - 52
JENNIFER BEAUVARLET ET AL: "Supplementary files - Triarylpyridine Compounds and Chloroquine Act in Concert to Trigger Lysosomal Membrane Permeabilization and Cell Death in Cancer Cells", CANCERS, vol. 12, no. 6, 18 June 2020 (2020-06-18), pages 1621, XP055716190, DOI: 10.3390/cancers12061621 *
JENNIFER BEAUVARLET ET AL: "Triarylpyridine Compounds and Chloroquine Act in Concert to Trigger Lysosomal Membrane Permeabilization and Cell Death in Cancer Cells", CANCERS, vol. 12, no. 6, 18 June 2020 (2020-06-18), pages 1621, XP055716187, DOI: 10.3390/cancers12061621 *
KANG C-CHUANG W-CKOUH C-WWANG Z-FCHO C-CCHANG C-C ET AL.: "Chemical principles for the design of a novel fluorescent probe with high cancer-targeting selectivity and sensitivity", INTEGR BIOL QUANT BIOSCI NANO MACRO, vol. 5, 2013, pages 1217 - 1228
KAZMI ET AL., DRUG METAB DISPOS, vol. 41, 2013, pages 897 - 905
KAZMI FHENSLEY TPOPE CFUNK RSLOEWEN GJBUCKLEY DB ET AL.: "Lysosomal Sequestration (Trapping) of Lipophilic Amine (Cationic Amphiphilic) Drugs in Immortalized Human Hepatocytes (Fa2N-4 Cells", DRUG METAB DISPOS, vol. 41, 2013, pages 897 - 905, XP055481523, DOI: 10.1124/dmd.112.050054
KROEMER GGALLUZZI L: "Lysosome-targeting agents in cancer therapy", ONCOTARGET, vol. 8, 2017, pages 112168 - 112169
KUZU O.F.TOPRAK M.NOORY A.M.ROBERTSON G.P.: "Effect of lysosomotropic molecules on cellular homeostasis", PHARMACOLOGICAL RESEARCH, vol. 117, 2017, pages 177 - 184, XP029921246, DOI: 10.1016/j.phrs.2016.12.021
LI QXIANG JFZHANG HTANG YL: "Searching Drug-Like Anti-cancer Compound(s) Based on G-Quadruplex Ligands", CURRENT PHARMACEUTICAL DESIGN, vol. 18, 2012, pages 1973 - 1983, XP055716818, DOI: 10.2174/138161212799958369
LIEBERMAN, PHARMACEUTICAL DOSAGE FORMS, vol. 1-3, 1992
LIM J.K.PADGETT C.S.VON HOFF D.D.PAPADOPOULOS K.P., JOURNAL OF CLINICAL ONCOLOGY, vol. 26, no. 15, 20 May 2008 (2008-05-20), pages 14667 - 14667
LLOYD, THE ART, SCIENCE AND TECHNOLOGY OF PHARMACEUTICAL COMPOUNDING, 1999
MARTINEZ ET AL., METHODS MOL BIOL, vol. 1064, 2013, pages 211 - 226
MARTINEZ R.BURRAGE A.M.WIETHOFF C.M.WODRICH H.: "High temporal resolution imaging reveals endosomal membrane penetration and escape of adenoviruses in real-time", METHODS MOL BIOL., vol. 1064, 2013, pages 211 - 226
MONTESPAN CMARVIN SAAUSTIN SBURRAGE AMROGER BRAYNE F ET AL.: "Multilayered control of Galectin-8 mediated autophagy during adenovirus cell entry through a conserved PPxY motif in the viral capsid", PLOS PATHOG, vol. 13, 2017, pages e1006217
MONTESPAN ET AL., PLOS PATHOG, vol. 13, 2017, pages e1006217
N. M. SMITH ET AL: "Unraveling the relationship between structure and stabilization of triarylpyridines as G-quadruplex binding ligands", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 9, no. 17, 1 January 2011 (2011-01-01), pages 6154, XP055717040, ISSN: 1477-0520, DOI: 10.1039/c1ob05560g *
NADANACIVA ET AL., TOXICOLOGY IN VITRO, vol. 25, no. 3, 2011, pages 715 - 723
O'PREY ET AL., METHODS ENZYMOL, vol. 588, 2017, pages 79 - 108
O'PREY JSAKAMAKI JBAUDOT ADNEW MVAN ACKER TTOOZE SA ET AL.: "Application of CRISPR/Cas9 to Autophagy Research", METHODS ENZYMOL, vol. 588, 2017, pages 79 - 108
PANDA DSAHA PDAS TDASH J: "Target guided synthesis using DNA nano-templates for selectively assembling a G-quadruplex binding c-MYC inhibitor", NAT COMMUN, vol. 8, 14 July 2017 (2017-07-14), pages 16103
PANDA ET AL., NAT COMMUN, vol. 8, 2017, pages 16103
PIAO ET AL., ANN N Y ACAD SCI, vol. 1371, 2016, pages 45 - 54
PIAO SAMARAVADI RK: "Targeting the lysosome in cancer", ANN N YACAD SCI, vol. 1371, 2016, pages 45 - 54
PICKAR, DOSAGE CALCULATIONS, 1999
QIAN LI ET AL: "Searching Drug-Like Anti-cancer Compound(s) Based on G-Quadruplex Ligands", CURRENT PHARMACEUTICAL DESIGN, vol. 18, no. 14, 1 March 2012 (2012-03-01), NL, pages 1973 - 1983, XP055716818, ISSN: 1381-6128, DOI: 10.2174/138161212799958369 *
SCHNEIDER ET AL., IMAGEJ SOFTWARE, vol. 9, no. 7, 2012, pages 671 - 675
SCHNEIDER, C. A.RASBAND, W. S.ELICEIRI, K. W.: "NIH Image to ImageJ: 25 years of image analysis", NATURE METHODS, vol. 9, no. 7, 2012, pages 671 - 675, XP055403257
SENGUPTA AGANGULY ACHOWDHURY S: "Promise of G-Quadruplex Structure Binding Ligands as Epigenetic Modifiers with Anti-Cancer Effects", MOLECULES, vol. 254, 2019, pages 582
SEO I.JHA B.K.LIM JG.SUH SI.SUH MH.BAEK WK.: "Identification of lysosomotropic compounds based on the distribution and size of lysosomes", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 450, no. 1, 2014, pages 189 - 194, XP029037873, DOI: 10.1016/j.bbrc.2014.05.091
SHIVALINGAM AIZQUIERDO MALE MAROIS AVYSNIAUSKAS ASUHLING KKUIMOVA MK ET AL.: "The interactions between a small molecule and G-quadruplexes are visualized by fluorescence lifetime imaging microscopy", NAT COMMUN, vol. 6, 2015, pages 8178
SMITH NMLABRUNIE GCORRY BTRAN PLNORRET MDJAVAHERI-MERGNY MRASTON CLMERGNY JL: "Unraveling the relationship between structure and stabilization of triarylpyridines as G-quadruplex binding ligands", ORG BIOMOL CHEM., vol. 9, no. 17, 2011, pages 6154 - 6220, XP055717040, DOI: 10.1039/c1ob05560g
SMITH PJSYKES HRFOX MEFURLONG IJ: "Subcellular distribution of the anticancer drug mitoxantrone in human and drug-resistant murine cells analyzed by flow cytometry and confocal microscopy and its relationship to the induction of DNA damage", CANCER RES, vol. 52, 1992, pages 4000 - 4008, XP055401531
SUN DLIU YYU QLIU DZHOU YLIU J: "Selective nuclei accumulation of ruthenium (II) complex enantiomers that target G-quadruplex DNA", J INORG BIOCHEM., vol. 150, 2015, pages 90 - 99, XP029322846, DOI: 10.1016/j.jinorgbio.2015.04.003
SUN DONGDONG ET AL: "Selective nuclei accumulation of ruthenium(II) complex enantiomers that target G-quadruplex DNA", JOURNAL OF INORGANIC BIOCHEMISTRY, ELSEVIER INC, US, vol. 150, 11 April 2015 (2015-04-11), pages 90 - 99, XP029322846, ISSN: 0162-0134, DOI: 10.1016/J.JINORGBIO.2015.04.003 *
SUN ET AL., J INORG BIOCHEM, 2015
ZHITOMIRSKY BASSARAF YG: "Lysosomal sequestration of hydrophobic weak base chemotherapeutics triggers lysosomal biogenesis and lysosome-dependent cancer multidrug resistance", ONCOTARGET, vol. 6, 2015, pages 1143 - 1156
ZHI-YIN SUN ET AL: "Developing Novel G-Quadruplex Ligands: from Interaction with Nucleic Acids to Interfering with Nucleic Acid-Protein Interaction", MOLECULES, vol. 24, no. 3, 22 January 2019 (2019-01-22), pages 396, XP055716258, DOI: 10.3390/molecules24030396 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113387934A (zh) * 2021-06-07 2021-09-14 中山大学 一种多芳基取代咪唑衍生物及其制备方法与应用
CN113387934B (zh) * 2021-06-07 2023-03-07 中山大学 一种多芳基取代咪唑衍生物及其制备方法与应用

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