WO2019129235A1 - E3连接酶抑制剂和溶瘤病毒在制备抗肿瘤药物的应用 - Google Patents

E3连接酶抑制剂和溶瘤病毒在制备抗肿瘤药物的应用 Download PDF

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WO2019129235A1
WO2019129235A1 PCT/CN2018/125016 CN2018125016W WO2019129235A1 WO 2019129235 A1 WO2019129235 A1 WO 2019129235A1 CN 2018125016 W CN2018125016 W CN 2018125016W WO 2019129235 A1 WO2019129235 A1 WO 2019129235A1
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ligase
virus
inhibitor
group
ligase inhibitor
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French (fr)
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颜光美
蔡静
朱文博
张海鹏
林园
梁剑开
龚守芳
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广州威溶特医药科技有限公司
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    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A61K35/768—Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the invention belongs to the field of biomedicine and relates to the application of the combination of an E3 ligase inhibitor and an oncolytic virus in the preparation of an antitumor drug.
  • Oncolytic virus is a type of replicable virus that selectively infects and kills tumor cells without damaging normal cells.
  • Oncolytic virotherapy is an innovative tumor-targeted therapeutic strategy that uses natural or genetically engineered viruses to selectively infect tumor cells and replicate in tumor cells for targeted lysis. Kills the role of tumor cells, but does not damage normal cells.
  • the M1 virus (Alphavirus M1) belongs to the genus Alphavirus, and has a good application effect in the preparation of antitumor drugs.
  • Chinese invention patent application 201410425510.3 discloses that the M1 virus can selectively cause tumor cell death without affecting normal cell survival, and has a very good application prospect in anti-tumor.
  • different tumors have different sensitivities to the M1 virus. For some tumors, when the M1 virus is administered alone, the oncolytic effect is not ideal.
  • M1 when used as an anti-tumor drug, M1 is less effective for colorectal cancer, liver cancer, bladder cancer and breast cancer than pancreatic cancer, nasopharyngeal cancer, prostate cancer and melanoma; Tumor, cervical cancer, and lung cancer are second, while gastric cancer is the least significant.
  • Compounds that screen to increase the therapeutic effect of oncolytic virus tumors are expected to increase the antitumor profile and antitumor strength of oncolytic viruses.
  • One of the objects of the present invention is to provide an use of an E3 ligase inhibitor for the preparation of an oncolytic virus anti-tumor synergist.
  • Another object of the present invention is to provide an antitumor pharmaceutical composition which allows the oncolytic virus to exert a better antitumor effect.
  • Another object of the present invention is to provide a safe and effective oncolytic virus potentiating drug against tumors which are insensitive to oncolytic viruses.
  • the E3 ligase inhibitor is a substance that inhibits the activity of E3 ligase, or a substance that degrades E3 ligase, or a gene tool that lowers the level of E3 ligase.
  • Protein ubiquitination plays a crucial role in maintaining cell stability and regulating a variety of biological processes, including the cell cycle, and its systemic dysfunction is closely related to the production and development of a variety of tumors, such as breast cancer.
  • the protein ubiquitination process is followed by three enzymes, including ubiquitin activating enzyme (E1), ubiquitin ligase (E2) and ubiquitin ligase (E3).
  • E3 ubiquitin ligase determines the specificity of ubiquitinated substrates, and a large number of studies suggest that it may be an effective target for tumor targeted therapy.
  • the inventors can significantly enhance the oncolytic effect of oncolytic viruses by inhibiting E3 ligase.
  • the inventors used a compound that inhibits the activity of E3 ligase, Thalidomide synergistic oncolytic virus, especially M1 virus, to act on tumor cells.
  • Thalidomide can synergize with oncolytic virus to enhance antitumor effect.
  • the present invention finds for the first time that an E3 ligase inhibitor can be used as an antitumor synergist/drug resistance reversal agent for oncolytic viruses.
  • the drug resistance reversal agent means that when some oncolytic viruses are used as anti-tumor drugs for treating tumors, some tumors are not sensitive to oncolytic viruses, or these tumors are resistant to oncolytic viruses.
  • a combination of an E3 ligase inhibitor (as a drug resistance reversal agent) with an oncolytic virus can be used to reverse the tumor's resistance to the oncolytic virus.
  • the present invention provides the use of an E3 ligase inhibitor for the preparation of an oncolytic virus anti-tumor synergist/drug reversal agent.
  • the E3 ligase inhibitor is selected from the group consisting of; preferably, the E3 ligase inhibitor includes, but is not limited to, the following compound or a derivative thereof having an E3 ligase inhibitory effect, or a pharmaceutically acceptable salt thereof, Solvates, tautomers, isomers: Thalidomide, NSC 207895, and the like which inhibit the activity of E3 ligase.
  • the manner in which the compound is obtained may be selected from, but not limited to, chemical separation or synthesis by itself or from commercial sources.
  • the E3 ligase inhibitor is Thalidomide, and the structural formula is as shown in Formula 1:
  • the E3 ligase inhibitor is NSC 207895, and the structural formula is as shown in Formula 2:
  • the E3 ligase inhibitor further comprises a tool for inhibition of E3 ligase gene expression, including but not limited to genes, gene silencing, and gene editing or knockout.
  • the E3 ligase inhibitor is selected from the group consisting of DNA, RNA, PNA or DNA-RNA-hybrid. They can be single-stranded or double-stranded.
  • E3 ligase inhibitors may include small inhibitory nucleic acid molecules such as short interfering RNA (siRNA), double stranded RNA (dsRNA), microRNA (miRNA), ribozyme, and small hairpin RNA (shRNA), all of which are attenuated Or eliminate the expression of E3 ligase.
  • siRNA short interfering RNA
  • dsRNA double stranded RNA
  • miRNA microRNA
  • ribozyme ribozyme
  • shRNA small hairpin RNA
  • the E3 ligase inhibitor further comprises one or more of an antibody, an antibody functional fragment, a peptide, and a peptidomimetic.
  • the antibody may be a monoclonal antibody, a polyclonal antibody, a multivalent antibody, a multispecific antibody (eg, a bispecific antibody), and/or an antibody fragment ligated to the E3 ligase.
  • the antibody may be a chimeric antibody, a humanized antibody, a CDR-grafted antibody or a human-type antibody.
  • the antibody fragment may be, for example, Fab, Fab', F(ab')2, Fv, Fd, single-chain Fv (scFv), a disulfide-bonded FV (sdFv), or a VL, VH domain.
  • the antibody may be in a conjugated form, for example, in combination with a label, a detectable label, or a cytotoxic agent.
  • the antibody may be a homotypic IgG (eg, IgGl, IgG2, IgG3, IgG4), IgA, IgM, IgE or IgD.
  • the oncolytic virus is selected from one or more of the group consisting of an alphavirus, an adenovirus, a vaccinia virus, a measles virus, a vesicular stomatitis virus, and a herpes simplex virus; wherein the alphavirus is selected from the group consisting of an M1 virus, Gaeta virus.
  • the oncolytic virus is selected from the group consisting of an M1 virus, a Gaeta virus, or a combination thereof.
  • the oncolytic viruses may specifically refer to an existing oncolytic virus, but also Some natural mutations that may occur or viruses that have undergone mutations (natural mutations, mandatory mutations, or selective mutations), genetic modifications, sequence additions or deletions, or partial replacements are not excluded.
  • the oncolytic viruses described herein include viruses that have undergone the above changes. Preferably, the above changes do not affect the effect of said oncolytic virus as described herein.
  • the E3 ligase inhibitor is a substance (for example, a compound, or an amino acid sequence, a nucleotide sequence, etc.) or a tool capable of knocking down or affecting the expression of an E3 ligase gene or reducing the amount or activity of an E3 ligase.
  • a person skilled in the art can modify, replace, change, etc. a compound or a gene tool thereof, but the E3 ligase inhibitor belonging to the present invention belongs to the above substances, compounds or tools as long as it functions as the above-mentioned inhibitor of E3 ligase. Homogeneous replacement.
  • the alphavirus is the M1 virus deposited under the accession number CCTCC V201423 (as deposited with the China Center for Type Culture Collection, deposited on July 17, 2014).
  • Genbank Accession No. EF011023 records a sequence of M1.
  • the Gita virus is a virus having a homology of up to 97.8% (Wen et al. Virus Genes. 2007; 35(3): 597-603) with the M1 virus, and the two have a high identity, and the M1 virus is also somewhat
  • the literature is classified as a Gaetavirus. Both can be expected to have the same efficacy.
  • a single alphavirus strain can also be administered. In other embodiments, a variety of strains and/or types of alphaviruses can also be used.
  • the invention also provides a pharmaceutical composition for treating a tumor comprising an E3 ligase inhibitor and an oncolytic virus.
  • the invention also provides a pharmaceutical kit for treating a tumor comprising an E3 ligase inhibitor or a derivative thereof or a combination thereof, and an oncolytic virus.
  • the drug kit differs from the composition in that the E3 ligase inhibitor is different from the oncolytic virus dosage form, but is packaged separately (eg, in a pill, or in a capsule, or in a tablet or vial containing an E3 ligase inhibitor; Additional pills, or capsules, or tablets or vials contain oncolytic viruses).
  • an oncolytic virus, an E3 ligase inhibitor, and a combination of an oncolytic virus and an E3 ligase inhibitor may also contain one or more adjuvants.
  • the adjuvant refers to an ingredient which can assist the therapeutic effect of the drug in the composition of the drug.
  • the drug kit can also contain individually packaged E3 ligase inhibitors, as well as individually packaged oncolytic viruses.
  • the E3 ligase inhibitor in the drug kit, and the administration of the oncolytic virus may be administered simultaneously or in any anterior-posterior sequence, such as administration of an E3 ligase inhibitor prior to the oncolytic virus, or administration of E3 following the oncolytic virus.
  • the patient can be a mammal. In some embodiments, the mammal can be a human.
  • the E3 ligase inhibitors include, but are not limited to, Thalidomide (Formula 1) or NSC 207895 (Formula 2), a compound that inhibits E3 ligase activity. Or targeting E3 ligase gene expression inhibition tools, including but not limited to gene interference, gene silencing, and gene editing or knockout tools.
  • the E3 ligase inhibitor is selected from the group consisting of Thalidomide.
  • the oncolytic virus is selected from one or more of the group consisting of an alphavirus, an adenovirus, a vaccinia virus, a measles virus, a vesicular stomatitis virus, and a herpes simplex virus; wherein the alphavirus is selected from the group consisting of an M1 virus and Gaeta virus. In a preferred embodiment, the oncolytic virus is selected from at least one of an M1 virus and a Gata virus.
  • the ratio of Thalidomide or NSC 207895 to oncolytic virus is optionally: 0.01 to 200 mg: 10 3 to 10 9 PFU; preferably 0.1 to 200 mg: 10 4 to 10 9 PFU; further preferably 0.1. ⁇ 100mg: 10 5 ⁇ 10 9 PFU.
  • the dosage is: Thalidomide or NSC 207895 is used in the range of 0.01 mg/kg to 200 mg/kg, and the oncolytic virus uses a titer of MOI from 10 3 to 10 9 (PFU/kg); preferably Thalidomide or NSC 207895 is used in the range of 0.1 mg/kg to 200 mg/kg, while the oncolytic virus uses a titer of MOI from 10 4 to 10 9 (PFU/kg); more preferably Thalidomide or NSC 207895 is used in a range of 0.1 mg/kg to 100 mg/kg.
  • the tumor virus uses a titer of MOI from 10 5 to 10 9 (PFU/kg).
  • the oncolytic virus is selected from one or more of the group consisting of an alphavirus, an adenovirus, a vaccinia virus, a measles virus, a vesicular stomatitis virus, and a herpes simplex virus; wherein the alphavirus is selected from the group consisting of an M1 virus and Gaeta virus.
  • the oncolytic virus is selected from at least one of an M1 virus and a Gata virus.
  • the M1 virus belongs to the Gaeta-like virus, and the homology of the two is as high as 97.8%.
  • the oncolytic virus employed is the M1 virus of accession number CCTCC V201423.
  • the tumor is a solid tumor or a hematoma.
  • the solid tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal cancer, lung cancer, or gastric cancer.
  • the tumor is a tumor that is insensitive to oncolytic viruses.
  • the tumor is a tumor that is insensitive to Ml oncolytic virus.
  • the Thalidomide or NSC 207895 provided by the present invention may be an injection, a tablet, a capsule, a patch, a kit, or the like.
  • the synergistic drug of the present invention is an injection; preferably, intravenous injection can be employed.
  • an E3 ligase inhibitor particularly Thalidomide
  • an E3 ligase inhibitor can increase the antitumor effect of oncolytic viruses to enhance the therapeutic effectiveness of oncolytic viruses as antitumor drugs.
  • Cytological experiments show that the combination of M1 virus and Thalidomide can significantly cause morphological lesions of tumor cells, thereby significantly enhancing the inhibition of tumor cells.
  • Thalidomide and M1 virus on human hepatocellular carcinoma Hep3B strain. It was unexpectedly found that the combination of antiviral compound Thalidomide and M1 virus significantly increased tumor cell morphology and significantly reduced tumor cell survival rate.
  • the oncolytic effect was significantly improved when Thalidomide was combined with M1.
  • the present invention finds that Thalidomide and oncolytic virus are combined to treat tumor cells, and the killing effect on tumor cells is significantly better than that of Thalidomide alone.
  • Thalidomide alone
  • the tumor cell survival rate is still as high as 83.6.
  • the tumor cell survival rate dropped significantly to 46.2%. It can be seen that the greatly enhanced oncolytic effect of Thalidomide in combination with M1 is due to the synergistic mechanism between Thalidomide and M1 virus, and does not simply act through the anti-tumor mechanism of Thalidomide.
  • Selected from in the specification is connected to the selected object, and can be understood as, for example, "X is selected from: A, B, C, ..., E” or "X is selected from: A, B, C, ... and One or more of E, etc., can be understood to include X, one of A, B, C, ... E, or any combination of the two, or any combination of the plurality. It is not excluded at this time that X also includes some other categories of substances.
  • the inhibitor of the present invention may be selected from E3 ligase inhibitors which are well known in the prior art, or substances which have been found to have an E3 ligase inhibitory effect by subsequent studies.
  • Hep3B Human hepatocellular carcinoma Hep3B (purchased from ATCC), M1 virus (Accession No. CCTCC V201423), high glucose DMEM medium (purchased from Corning), automatic enzyme-linked detection microplate reader, Thalidomide (purchased from Selleckchem: S1193).
  • MTT and intracellular succinate dehydrogenase reaction when cultured to 48h, add 20 ⁇ l (5mg/ml) of MTT to each well and continue to incubate for 4 hours. At this time, microscopically formed granular particles can be observed in living cells. Blue-purple nails crystallize.

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Abstract

E3连接酶抑制剂和溶瘤病毒在制备抗肿瘤药物的应用。E3连接酶抑制剂可以用于制备溶瘤病毒抗肿瘤增效剂。一种包含E3连接酶抑制剂以及溶瘤病毒的药物组合物，包含E3连接酶抑制剂及溶瘤病毒的药品套装，以及E3连接酶抑制剂与溶瘤病毒在治疗肿瘤，特别是对所述溶瘤病毒不敏感的肿瘤中的用途。

Description

E3连接酶抑制剂和溶瘤病毒在制备抗肿瘤药物的应用 技术领域
本发明属于生物医药领域，涉及E3连接酶抑制剂与溶瘤病毒的联合在制备抗肿瘤药物中的应用。
背景技术
溶瘤病毒(oncolytic virus)是一类选择性的感染并杀伤肿瘤细胞，而不损伤正常细胞的可复制病毒。溶瘤病毒疗法(oncolytic virotherapy)是一种创新的肿瘤靶向治疗策略，它利用天然的或经基因工程改造的病毒选择性的感染肿瘤细胞，并在肿瘤细胞中复制，达到靶向性溶解、杀伤肿瘤细胞的作用，但是对正常细胞没有损伤。
M1病毒(Alphavirus M1)属于甲病毒属(Alphavirus)，其在制备抗肿瘤药物方面具有较好的应用效果。例如中国发明专利申请201410425510.3公开了M1病毒能选择性引起肿瘤细胞死亡而不影响正常细胞存活，其在抗肿瘤方面具有非常好的应用前景。然而，不同肿瘤对M1病毒的敏感性不一，对于某些肿瘤，M1病毒单独用药时，溶瘤作用还不够理想。例如中国发明专利申请201410425510.3所记载的，M1作为抗肿瘤药物使用时，对于结直肠癌、肝癌、膀胱癌和乳腺癌的效果不如胰腺癌、鼻咽癌、前列腺癌和黑色素瘤明显；而胶质瘤、宫颈癌、肺癌则更其次；而胃癌则最不显著。筛选增加溶瘤病毒肿瘤治疗效果的化合物有望增加溶瘤病毒的抗瘤谱及抗瘤强度。
发明内容
本发明的目的之一在于提供一种E3连接酶抑制剂在制备溶瘤病毒抗瘤增效剂方面的应用。
本发明的另一个目的在于提供一种抗瘤药物组合物，其可以使得溶瘤病毒发挥更好的抗瘤效果。
本发明的另一个目的在于提供一种针对溶瘤病毒不敏感的肿瘤，安全有效的溶瘤病毒增效药物。
发明通过以下技术方案实现上述目的：
发明人通过研究、筛选发现，E3连接酶抑制剂出人意料地可以增强溶瘤病毒的溶瘤效果。
所述的E3连接酶抑制剂为抑制E3连接酶活性的物质、或降解E3连接酶的物质、或降低E3连接酶水平的基因工具。
蛋白泛素化在维持细胞稳定性和调控多种生物学过程(包括细胞周期)中起着至关重要的作用，其系统功能紊乱与多种肿瘤(如乳腺癌等)产生和发展关系密切。蛋白泛素化过程由三种酶依次催化完成，包括泛素激活酶(E1)、泛素连接酶(E2)和泛素连接酶(E3)。E3泛素连接酶决定了泛素化底物的特异性，大量研究表明其可能是肿瘤靶向治疗的有效靶标。
发明人通过抑制E3连接酶可以显著增强溶瘤病毒的溶瘤效应。发明人采用了抑制E3连接酶活性的化合物Thalidomide协同溶瘤病毒尤其是M1病毒作用于肿瘤细胞，实验结果发现，Thalidomide可以协同溶瘤病毒增强抗肿瘤效应。
本发明首次发现，E3连接酶抑制剂可以作为溶瘤病毒的抗瘤增效剂/耐药逆转剂。
耐药逆转剂是指，当采用一些溶瘤病毒作为抗肿瘤药物用于治疗肿瘤时，存在着一些肿瘤对溶瘤病毒并不太敏感，或者说这些肿瘤对溶瘤病毒具有抗性，此时，可以采用与E3连接酶抑制剂(作为耐药逆转剂)联用溶瘤病毒的方式，以逆转肿瘤对所述溶瘤病毒的抗性。
本发明提供了E3连接酶抑制剂在制备溶瘤病毒抗瘤增效剂/耐药逆转剂方面的应用。
所述的E3连接酶抑制剂选自化合物；优选地，所述的E3连接酶抑制剂包 括但不限于以下化合物或其具有E3连接酶抑制作用的衍生物、或其药学上可接受的盐、溶剂化物、互变异构体、同分异构体：Thalidomide、NSC 207895等抑制E3连接酶活性的化合物。化合物的获取方式可选但不限于：自己化学分离或合成或者从商业途径购买。
在本发明一优选的实施例中，E3连接酶抑制剂为Thalidomide，其结构式如式1所示：
Figure PCTCN2018125016-appb-000001
在本发明另一优选的实施例中，E3连接酶抑制剂为NSC 207895，其结构式如式2所示：
Figure PCTCN2018125016-appb-000002
或者，所述的E3连接酶抑制剂还包括针对E3连接酶基因表达抑制工具，包括但不限于基因、基因沉默以及基因编辑或敲除等工具手段。
作为一种可选的实施方式，所述E3连接酶抑制剂选自DNA、RNA、PNA或DNA-RNA-杂合体。它们可以是单链的或双链的。
E3连接酶抑制剂可包括一些小的抑制核酸分子，例如短干扰RNA(siRNA)，双链RNA(dsRNA)，microRNA(miRNA)，核酶，以及小发夹RNA(shRNA)， 这些都能减弱或消除E3连接酶的表达。
或者，所述的E3连接酶抑制剂还包括抗体、抗体功能性片段、肽类、和拟肽类中的一种或几种。其中，所述的抗体可能是单克隆抗体，多克隆抗体，多价抗体，多特异性抗体(例如：双特异性抗体)，和/或连接在E3连接酶上的抗体片段。该抗体可以是嵌合抗体、人源化抗体、CDR移植抗体或人型抗体。抗体片段可以是，例如，Fab，Fab’，F(ab’)2，Fv，Fd，单链Fv(scFv)，具二硫键的FV(sdFv)，或VL、VH结构域。抗体可能是一个共轭的形式，例如，结合一个标签、一个可检测标记，或一种细胞毒性剂。抗体可能是同型IgG(例如：IgG1、IgG2、IgG3、IgG4)、IgA、IgM、IgE或IgD。
所述的溶瘤病毒选自甲病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒中的一种或多种；其中，所述的甲病毒选自M1病毒、盖塔病毒。作为优选的实施方式，所述的溶瘤病毒选自M1病毒、盖塔病毒或者它们的组合。
本发明所说的溶瘤病毒(M1病毒、盖塔病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒)可以尤其地指目前已有的溶瘤病毒，但也不排除一些可能发生的自然变异或者进行了突变(自然突变、强制性突变、或选择性突变)、基因修饰、序列增加或删除或部分替换的病毒。这里所述的溶瘤病毒包括已经进行了上述改变的病毒。最好是上述改变并不影响所说的溶瘤病毒发挥本发明所述的作用。所说的E3连接酶抑制剂为能起到敲低或影响E3连接酶基因表达或者降低E3连接酶量或活性的物质(例如化合物、或氨基酸序列、核苷酸序列等)或工具等。本领域技术人员可以对其抑制化合物或者基因工具进行修饰、替换、改变等，但只要起到上述抑制E3连接酶作用的，则属于本发明的E3连接酶抑制剂，属于上述物质、化合物或工具等的同质替换。
在一些实施例中，甲病毒是保藏编号CCTCC V201423(保藏于中国典型培养物保藏中心，保藏日期2014年7月17日)的M1病毒。作为很可能来源于同一毒株的病毒，Genbank Accession No.EF011023记录了一株M1的序列。盖塔病 毒作为与M1病毒具有高达97.8％(Wen et al.Virus Genes.2007；35(3):597-603)同源性的病毒，两者具有很高的同一性，M1病毒也被一些文献归类为类盖塔病毒。可以预期二者具有相同的功效。单个甲病毒株也可以施用。在其他实施方案中，也可使用多种菌株和/或类型的甲病毒。
本发明还提供一种用于治疗肿瘤的药物组合物，其包含E3连接酶抑制剂以及溶瘤病毒。本发明还提供用于治疗肿瘤的药品套装，其包含E3连接酶抑制剂或其衍生物或它们的组合，以及溶瘤病毒。药品套装区别于组合物的地方在于，E3连接酶抑制剂不同于溶瘤病毒的剂型，而是独立包装(例如：药丸、或胶囊、或药片或安剖瓶中，含有E3连接酶抑制剂；另外的药丸、或胶囊、或药片或安剖瓶中，含有溶瘤病毒)。在一些实施例中，溶瘤病毒、E3连接酶抑制剂，以及溶瘤病毒和E3连接酶抑制剂的组合，也可含一种或多种佐剂。所述的佐剂是指在药物组成中，可辅助药物疗效的成分。药品套装也可以包含独立包装的E3连接酶抑制剂，以及独立包装的溶瘤病毒。药物套装中E3连接酶抑制剂，以及溶瘤病毒的施用，可以是同时施用或者是以任意的前后顺序施用，例如在溶瘤病毒之前施用E3连接酶抑制剂，或者在溶瘤病毒之后施用E3连接酶抑制剂，或者两者同时施用。在各种实施例中，患者可以是哺乳动物。在一些实施例中，哺乳动物可以是人。
所述的E3连接酶抑制剂包括但不限于Thalidomide(式1)或NSC 207895(式2)这一类的抑制E3连接酶活性的化合物。或者针对E3连接酶基因表达抑制工具，包括但不限于基因干扰、基因沉默以及基因编辑或敲除等工具手段。作为本发明优选的实施方式，所述的E3连接酶抑制剂选自Thalidomide。
所述的溶瘤病毒选自甲病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒中的一种或多种；其中，所述的甲病毒选自M1病毒和盖塔病毒。作为优选的实施方式，所述的溶瘤病毒选自M1病毒和盖塔病毒的至少一种。
在组合物或药品套装中，Thalidomide或NSC 207895与溶瘤病毒的配比可 选地为：0.01～200mg:10 3～10 9PFU；优选0.1～200mg:10 4～10 9PFU；进一步优选0.1～100mg:10 5～10 9PFU。
优选使用剂量为：Thalidomide或NSC 207895使用范围为0.01mg/kg至200mg/kg，同时溶瘤病毒使用滴度为MOI从10 3至10 9(PFU/kg)；优选Thalidomide或NSC 207895使用范围为0.1mg/kg至200mg/kg，同时溶瘤病毒使用滴度为MOI从10 4至10 9(PFU/kg)；更优选Thalidomide或NSC 207895使用范围为0.1mg/kg至100mg/kg，同时溶瘤病毒使用滴度为MOI从10 5至10 9(PFU/kg)。
所述的溶瘤病毒选自甲病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒中的一种或多种；其中，所述的甲病毒选自M1病毒和盖塔病毒。作为优选的实施方式，所述的溶瘤病毒选自M1病毒和盖塔病毒的至少一种。M1病毒属于盖塔相似病毒，这两者的同源性高达97.8％。
在本发明的一个实施例中，采用的溶瘤病毒为保藏编号CCTCC V201423的M1病毒。
在一个实施方式中，所述肿瘤为实体瘤或血液瘤。在一个实施方式中，所述实体瘤为肝癌、结直肠癌、膀胱癌、乳腺癌、宫颈癌、前列腺癌、胶质瘤、黑色素瘤、胰腺癌、鼻咽癌、肺癌、或胃癌。在优选的实施方式中，所述肿瘤为对溶瘤病毒不敏感的肿瘤。在更优选的实施方式中，所述肿瘤为对M1溶瘤病毒不敏感的肿瘤。
作为可选的实施方案，本发明所提供的Thalidomide或NSC 207895可以是注射剂、片剂、胶囊、贴剂、试剂盒等。作为优选的实施方案，本发明的增效药物是注射剂；优选地，可采用静脉注射。
作为本发明进一步优选的实施方案：本发明发现了E3连接酶抑制剂，尤其是Thalidomide可以增加溶瘤病毒的抗肿瘤效应，以提高溶瘤病毒作为抗肿瘤药物时的治疗有效性。细胞学实验证明M1病毒和Thalidomide联合应用，可显著引起肿瘤细胞的形态学病变，从而显著增强对肿瘤细胞的抑制作用。
我们联合Thalidomide和M1病毒作用于人肝细胞癌Hep3B株，出人意料的发现抗病毒化合物Thalidomide和M1病毒联合应用时，显著增加肿瘤细胞形态病变，显著降低肿瘤细胞生存率。例如在本发明的一个实施例中，当M1病毒(MOI＝0.001)单独处理肝癌细胞时，肿瘤细胞存活率为79.9％，而当以50μM的Thalidomide与同样MOI的M1病毒联用时，肿瘤细胞存活率大幅下降至46.2％。与单用M1病毒的抗肿瘤效果相比，Thalidomide与M1联用时，溶瘤效果显著提升。
本发明发现，Thalidomide与溶瘤病毒联合应用处理肿瘤细胞，对肿瘤细胞杀伤作用显著优于单用相同浓度的Thalidomide，例如当同样例如以50μM的Thalidomide处理肿瘤细胞时，肿瘤细胞存活率仍高达83.6％，当以50μM的Thalidomide与M1病毒联用时，肿瘤细胞存活率大幅下降至46.2％。可见，Thalidomide与M1联用时大幅提升的溶瘤效果，是得益于Thalidomide与M1病毒之间的协同性机制，并非简单地通过Thalidomide的抗肿瘤机制发挥作用。
附图说明
图1 Thalidomide与M1病毒联合处理显著降低人肝细胞癌株Hep3B生存率；
具体实施方式
以下实施方式是对本发明作进一步说明，但本发明的实施方式不局限于以下的实施例介绍，凡依照本发明的原理或理念所作的等同的变化或变通都应视为本发明保护的范畴。
在没有特别指明的情况下，本发明采用的材料及实验方法为常规材料及方法。
说明书中的“选自”连接着所选对象，可以理解为，例如：“X选自：A、B、C、……、E”或“X选自：A、B、C、……和E中的一种或多种”，等等，均可理解为，X包括了A、B、C、……E中的一种、或者两者的任意组合、或者多 者的任意组合。此时不排除X还包括了一些其他类别的物质。
除了上述提及的特定E3连接酶抑制剂，本发明的抑制剂还可以选自现有技术中已经公知的E3连接酶抑制剂、或者经后续研究发现具备E3连接酶抑制作用的物质。
实施例1 Thalidomide与M1病毒联合处理显著降低人肝细胞癌株Hep3B生存率
材料：
人肝细胞癌Hep3B(购于ATCC)，M1病毒(保藏编号CCTCC V201423)，高糖DMEM培养基(购于Corning)，自动酶联检测酶标仪，Thalidomide(购于Selleckchem：S1193)。
方法：
a)接种细胞、给药处理：选择对数生长期细胞，DMEM完全培养液(含10％胎牛血清、1％双抗)制成细胞悬液，以每孔4×10 3/孔的密度接种在96孔培养板内。12小时后见细胞完全贴壁，实验分对照组，单独Thalidomide组，M1感染组和Thalidomide/M1联用组。所用剂量为：所用剂量为：M1病毒(MOI＝0.001)感染细胞；Thalidomide为50μM。
b)MTT与细胞内的琥珀酸脱氢酶反应：培养至48h时，每孔加入MTT 20μl(5mg/ml)，继续孵育4小时，此时镜检可观察到、活细胞内形成的颗粒状蓝紫色甲臜结晶。
c)溶解甲臜颗粒：小心吸去上清，加DMSO 100μl/孔溶解形成的结晶，在微型振荡器上震荡5min，然后在酶联检测仪上用波长570nm检测各孔的光密度(OD值)。细胞存活率＝药物处理组OD值/对照组OD值×100％。
结果:
如图1所示，M1病毒(MOI＝0.001)单独处理对肿瘤细胞Hep3B具有较小的 生存率抑制作用，肿瘤细胞存活率达到79.9％，50μM的Thalidomide处理组肿瘤细胞存活率仍高达83.6％，然而，当同样的50μM的Thalidomide与M1病毒(MOI＝0.001)联用(Thalidomide+M1)时，肿瘤细胞存活率大幅下降至46.2％。

Claims (9)

  1. E3连接酶抑制剂在制备溶瘤病毒抗肿瘤增效剂或耐药逆转剂方面的应用；
    优选地，所述的溶瘤病毒选自甲病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒中的一种或多种；
    优选地，所述的甲病毒选自M1病毒和盖塔病毒中的至少一种。
  2. 如权利要求1所述的应用，其特征在于，所述的E3连接酶抑制剂为抑制E3连接酶活性的物质、或降解E3连接酶的物质、或降低E3连接酶水平的基因工具、或它们的任意组合；
    优选地，所述的E3连接酶抑制剂选自化合物；
    更优选地，所述的E3连接酶抑制剂选自以下化合物或其具有E3连接酶抑制作用的衍生物、或其药学上可接受的盐、溶剂化物、互变异构体、同分异构体：Thalidomide、NSC 207895；
    更优选地，所述的Thalidomide的结构式如式1所示：
    Figure PCTCN2018125016-appb-100001
    更优选地，所述的NSC 207895的结构式如式2所示；
    Figure PCTCN2018125016-appb-100002
    或者优选地，所述的E3连接酶抑制剂选自抗体、抗体功能性片段、肽类、和拟肽类中的一种或几种；
    或者优选地，所述的E3连接酶抑制剂选自基因干扰、基因沉默、基因编辑或基因敲除材料；
    或者优选地，所述的E3连接酶抑制剂选自：DNA、RNA、PNA和DNA-RNA-杂合体中的一种或几种；
    更优选地，所述E3连接酶抑制剂选自：siRNA、dsRNA、miRNA、shRNA和核酶中的一种或几种；
    更优选地，所述的E3连接酶抑制剂为肿瘤靶向的抑制剂。
  3. 一种治疗肿瘤的药物组合物，包含：
    (a)E3连接酶抑制剂；
    所述的E3连接酶抑制剂为抑制E3连接酶活性的物质、或降解E3连接酶的物质、或降低E3连接酶水平的基因工具；
    优选地，所述的E3连接酶抑制剂选自化合物；
    更优选地，所述的E3连接酶抑制剂选自以下化合物或其具有E3连接酶抑制作用的衍生物、或其药学上可接受的盐、溶剂化物、互变异构体、同分异构体：Thalidomide、NSC 207895；
    更优选地，所述的Thalidomide的结构式如式1所示：
    Figure PCTCN2018125016-appb-100003
    更优选地，所述的NSC 207895的结构式如式2所示；
    Figure PCTCN2018125016-appb-100004
    或者优选地，所述的E3连接酶抑制剂选自抗体、抗体功能性片段、肽类、和拟肽类中的一种或几种；
    或者优选地，所述的E3连接酶抑制剂选自基因干扰、基因沉默、基因编辑或基因敲除材料、或它们的任意组合；
    或者优选地，所述的E3连接酶抑制剂选自：DNA、RNA、PNA和DNA-RNA-杂合体中的一种或几种；
    更优选地，所述E3连接酶抑制剂选自：siRNA、dsRNA、miRNA、shRNA和核酶中的一种或几种；
    更优选地，所述的E3连接酶抑制剂为肿瘤靶向的抑制剂；
    (b)溶瘤病毒；所述的溶瘤病毒选自甲病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒中的一种或多种；
    优选地，所述的甲病毒选自M1病毒和盖塔病毒中的至少一种。
  4. 一种药品套装，包含：
    (a)E3连接酶抑制剂；
    所述的E3连接酶抑制剂为抑制E3连接酶活性的物质、或降解E3连接酶的物质、或降低E3连接酶水平的基因工具；
    优选地，所述的E3连接酶抑制剂选自化合物；
    更优选地，所述的E3连接酶抑制剂选自以下化合物或其具有E3连接酶抑制作用的衍生物、或其药学上可接受的盐、溶剂化物、互变异构体、同分异构体：Thalidomide、NSC 207895；
    更优选地，所述的Thalidomide的结构式如式1所示：
    Figure PCTCN2018125016-appb-100005
    更优选地，所述的NSC 207895的结构式如式2所示；
    Figure PCTCN2018125016-appb-100006
    或者优选地，所述的E3连接酶抑制剂选自抗体、抗体功能性片段、肽类、和拟肽类中的一种或几种；
    或者优选地，所述的E3连接酶抑制剂选自基因干扰、基因沉默、基因编辑或基因敲除材料；
    或者优选地，所述的E3连接酶抑制剂选自：DNA、RNA、PNA和DNA-RNA-杂合体中的一种或几种；
    更优选地，所述E3连接酶抑制剂选自：siRNA、dsRNA、miRNA、shRNA和核酶中的一种或几种；
    更优选地，所述的E3连接酶抑制剂为肿瘤靶向的抑制剂；
    (b)溶瘤病毒；所述的溶瘤病毒选自甲病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒中的一种或多种；
    优选地，所述的甲病毒选自M1病毒和盖塔病毒中的至少一种；
    优选地，包含独立包装的E3连接酶抑制剂及独立包装的溶瘤病毒。
  5. E3连接酶抑制剂及溶瘤病毒的组合在制备治疗肿瘤药物中的应用；
    所述的溶瘤病毒选自甲病毒、腺病毒、牛痘病毒、麻疹病毒、水泡口炎病毒、和单纯性疱疹病毒中的一种或多种；
    优选地，所述的甲病毒选自M1病毒和盖塔病毒中的至少一种；
    所述的E3连接酶抑制剂为抑制E3连接酶活性的物质、或降解E3连接酶的物质、或降低E3连接酶水平的基因工具；
    优选地，所述的E3连接酶抑制剂选自化合物；
    更优选地，所述的E3连接酶抑制剂选自以下化合物或其具有E3连接酶抑制作用的衍生物、或其药学上可接受的盐、溶剂化物、互变异构体、同分异构体：Thalidomide、NSC 207895；
    更优选地，所述的Thalidomide的结构式如式1所示：
    Figure PCTCN2018125016-appb-100007
    更优选地，所述的NSC 207895的结构式如式2所示；
    Figure PCTCN2018125016-appb-100008
    或者优选地，所述的E3连接酶抑制剂选自抗体、抗体功能性片段、肽类、和拟肽类中的一种或几种；
    或者优选地，所述的E3连接酶抑制剂选自基因干扰、基因沉默、基因编辑或 基因敲除材料；
    或者优选地，所述的E3连接酶抑制剂选自：DNA、RNA、PNA和DNA-RNA-杂合体中的一种或几种；
    更优选地，所述E3连接酶抑制剂选自：siRNA、dsRNA、miRNA、shRNA和核酶中的一种或几种；
    更优选地，所述的E3连接酶抑制剂为肿瘤靶向的抑制剂。
  6. 根据权利要求3所述的组合物，其中所述药物组合物还包含药学上可接受的载体；所述载体优选地选自冻干粉针、注射剂、片剂、胶囊、试剂盒或贴剂。
  7. 如权利要求3、4或6任一所述的组合物/药品套装，其特征在于所述的Thalidomide或NSC 207895与溶瘤病毒的配比为：0.01～200mg:10 3～10 9PFU；
    优选0.1～200mg:10 4～10 9PFU；进一步优选0.1～100mg:10 5～10 9PFU；
    进一步优选地，使用剂量为：Thalidomide或NSC 207895使用范围为0.01mg/kg至200mg/kg，同时溶瘤病毒使用滴度为MOI从10 3至10 9(PFU/kg)；优选Thalidomide或NSC 207895使用范围为0.1mg/kg至200mg/kg，同时溶瘤病毒使用滴度为MOI从10 4至10 9(PFU/kg)；更优选Thalidomide或NSC 207895使用范围为0.1mg/kg至100mg/kg，同时溶瘤病毒使用滴度为MOI从10 5至10 9(PFU/kg)。
  8. 如权利要求1-7任一所述的应用/组合物/药品套装，其特征在于所述的E3连接酶抑制剂为Thalidomide和/或NSC 207895。
  9. 如权利要求1-8任一所述的应用/组合物/药品套装，其特征在于所述的肿瘤为实体瘤或血液瘤；优选地，所述的实体瘤为肝癌、结直肠癌、膀胱癌、乳腺癌、宫颈癌、前列腺癌、胶质瘤、黑色素瘤、胰腺癌、鼻咽癌、肺癌或胃癌；
    或者优选地，所述的肿瘤为对溶瘤病毒不敏感的肿瘤；
    更优选地，所述肿瘤为对溶瘤病毒不敏感的肝癌、结直肠癌、膀胱癌、乳腺癌、宫颈癌、前列腺癌、胶质瘤、黑色素瘤、胰腺癌、鼻咽癌、肺癌或胃癌。
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