WO2015161762A1 - 环二核苷酸cGAMP在抗肿瘤中的应用 - Google Patents

环二核苷酸cGAMP在抗肿瘤中的应用 Download PDF

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WO2015161762A1
WO2015161762A1 PCT/CN2015/076961 CN2015076961W WO2015161762A1 WO 2015161762 A1 WO2015161762 A1 WO 2015161762A1 CN 2015076961 W CN2015076961 W CN 2015076961W WO 2015161762 A1 WO2015161762 A1 WO 2015161762A1
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cancer
tumor
cgamp
cgmp
cell line
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French (fr)
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谭相石
李铁军
徐启明
潘洁
芮耀诚
程浩
章越凡
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复旦大学
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Priority to EP15783435.9A priority Critical patent/EP3135290B1/en
Priority to JP2016563423A priority patent/JP2017513869A/ja
Priority to US15/304,924 priority patent/US10092592B2/en
Publication of WO2015161762A1 publication Critical patent/WO2015161762A1/zh

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid

Definitions

  • the invention belongs to the technical field of biomedicine, and particularly relates to the application of a cyclic dinucleotide (cGAMP) in antitumor and in preparing antitumor drugs.
  • cGAMP cyclic dinucleotide
  • Tumor is one of the major diseases that seriously endanger human health. It is characterized by excessive cell proliferation and differentiation. WHO experts predict that the global population of cancer will reach 20 million in 2020, and the death toll will reach 12 million. The tumor will become the first human killer in this century and pose the most serious threat to human survival.
  • the incidence and mortality of lung cancer, colorectal cancer, gastric cancer, liver cancer, etc. are among the highest in all kinds of malignant tumors. According to the National Cancer Registry (2012 China Cancer Registration Annual Report), there are about 3.12 million new cases of cancer every year, an average of 8,550 people per day, and 6 people per minute are diagnosed with cancer in the country. Lung cancer, gastric cancer, colorectal cancer, liver cancer and esophageal cancer are among the top five cancers in the country. As the incidence and mortality of malignant tumors increase year by year, the demand for treatment of malignant tumors is increasing.
  • Chemotherapy is one of the effective ways to treat tumors.
  • the mechanism of action of traditional chemotherapeutic drugs is mainly to prevent the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) or protein, or directly affect these macromolecules, thereby inhibiting the proliferation and death of tumor cells.
  • Some drugs can also inhibit tumor growth by altering the hormone balance in the body.
  • anti-tumor drugs have been developed into 6 categories: 1 antimetabolites; 2 alkylating agents; 3 cytotoxic antibiotics; 4 plant alkaloids and other natural drugs; 5 anti-tumor hormones; 6 platinum and other anti-tumor drugs .
  • TKI small molecule tyrosine kinase inhibitors
  • other hot-acting mechanisms include immunostimulants, angiogenesis inhibitors, cell cycle inhibitors, immunosuppressants and stimulators, protein kinase inhibitors, and the like.
  • Microbial and viral DNA can induce an endogenous potent immune response by stimulating interferon secretion in infected mammalian cells.
  • the immune response of the endoplasmic reticulum (ER) receptor protein (STING) to cytoplasmic DNA is an essential factor.
  • ER endoplasmic reticulum
  • STING endoplasmic reticulum receptor protein
  • cGAMP cyclized cGMP-AMP dinucleotide synthetase
  • cGAMP is a cytoplasmic DNA sensor that acts as a second messenger to stimulate INF- ⁇ induction by STING, mediates the activation of TBK1 and IRF-3, and then initiates transcription of the INF- ⁇ gene.
  • cGAMP binds to STING, activates the transcription factor IRF3 and produces beta interferon.
  • the object of the present invention is also to propose the application of cGAMP in the preparation of antitumor drugs to prepare antitumor drugs with low toxicity and good effect.
  • cGAMP can inhibit the growth of a variety of tumor cells, has obvious anti-tumor effect, and can be used for preparing anti-tumor drugs.
  • the tumor includes, but is not limited to, gastric cancer, lung cancer, colon cancer, liver cancer, prostate cancer, pancreatic cancer and the like.
  • the invention also relates to antineoplastic agents prepared using cGAMP.
  • the prepared antitumor drug has low toxicity and good effect.
  • cGAMP (cyclized-GMP-AMP) was synthesized by cyclized cGMP-AMP dinucleotide synthetase (cGAS) under the activation conditions of DNA binding according to literature methods. The purity is above 98%. (PingweiLi, et al., Immunity, 2013, 39(6), 1019-1031.)
  • Example 2 Anti-tumor effect of cGAMP (cyclized-GMP-AMP)
  • the tumor-bearing mouse model was used to examine the inhibitory effect of cGAMP on the growth of subcutaneous xenografts in animals.
  • Solvent normal saline.
  • Preparation method Prepare a solution of the desired concentration with a physiological saline solution before use.
  • Test drug concentration 1 mg/ml, 4 mg/ml.
  • mice BALB/c nude mice, male, weighing 16-18g, 4-6 weeks old, SPF grade, purchased from Shanghai Slack Laboratory Animals Co., Ltd. [Experimental Animal Quality Certificate No.: SCXK (Shanghai) 2007-0005].
  • mice All nude mice were free to forage and drink and were housed at the Experimental Animal Center of a military medical university of the People's Liberation Army at room temperature (23 ⁇ 2) °C. Both the feed and the water were autoclaved, and all the experimental feeding processes were SPF grade.
  • cGAMP was intraperitoneally injected into mice, and two dose groups were set: 10 mg/kg, 40 mg/kg.
  • the cells were cultured and passaged, and the cells were collected in the log phase of the cells to prepare a cell suspension at a concentration of 1.0 ⁇ 10 7 /ml, and the right front limbs of the nude mice were injected with 0.2 ml of cell suspension (the number of cells was 2.0 ⁇ 10 6 /
  • the tumor grew to a diameter of about 5 mm for about 10 days, and the tumor was successful. It was randomly divided into 4 groups: negative control group (intraperitoneal saline group), 5-FU group (ipcreal injection 5-FU 20 mg/kg group), cGMP -AMP low dose group (intraperitoneal cGMP-AMP) 10 mg/kg.
  • the high dose group of cGMP-AMP group (intraperitoneal cGMP-AMP group) 40 mg/kg.
  • the drug was administered once a day for 14 days.
  • human gastric cancer cell line MNK-45 human gastric cancer cell line MNK-45
  • human lung adenocarcinoma cell line A549 human colon cancer cell line Lovo
  • human liver cancer cell line SMMC-7721 human prostate cancer cell line PC-3
  • human pancreatic cancer cell line SW1990 human pancreatic cancer cell line SW1990
  • Data were expressed as x ⁇ s, and were processed by SPSS10.0 software.
  • the subcutaneous xenograft model was successfully prepared by subcutaneous inoculation of tumor cells in nude mice. Both 5-FU and cGAMP could significantly inhibit tumor growth. The tumor weight after 14 days of administration was significantly lower than that of the negative control group (P ⁇ 0.05, P ⁇ 0.01). It indicates that cGAMP has an anti-tumor effect. The specific results are shown in Tables 1 to 6.
  • cGAMP was prepared from Example 1 and formulated into a solution having a concentration of 200 mg/mL with physiological saline.
  • mice were given a single tail vein injection of 10 ml/kg of cGAMP or 2 g/kg by weight, and the toxicity and death of the mice within 14 days after administration were observed. It was found that the mice were normal after a single tail vein injection. Within 14 days after the administration, the mice did not die. On the 15th day, all the mice were sacrificed, dissected, and each organ was visually inspected, and no obvious lesions were observed.

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Abstract

环二核苷酸cGMP在制备抗肿瘤的药物中的应用，其中所述肿瘤为胃癌、肺癌、结肠癌、肝癌、前列腺癌或胰腺癌。

Description

环二核苷酸cGAMP在抗肿瘤中的应用 技术领域
本发明属于生物医药技术领域，具体涉及一种环二核苷酸(cGAMP)在抗肿瘤中以及在制备抗肿瘤药物中的应用。
背景技术
肿瘤是一类严重危害人类生命健康的重大疾病之一，表现为细胞过度增殖和分化异常。WHO专家预测，2020年全球人口肿瘤发病将达到2 000万人，死亡人数将达到1 200万人，肿瘤将成为本世纪人类第一杀手，对人类生存构成最严重的威胁。肺癌、结/直肠癌、胃癌、肝癌等的发病率和死亡率均居各类恶性肿瘤的前列。据全国肿瘤登记中心发布的(2012中国肿瘤登记年报》统计，每年新发生肿瘤病例约为312万例，平均每天8 550人，全国每分钟有6人被诊断为癌症。从病种来看，肺癌、胃癌、结/直肠癌、肝癌和食管癌，居全国恶性肿瘤发病的前五位。随着恶性肿瘤发病率和死亡率的逐年增加，恶性肿瘤治疗需求越来越大。
化疗是治疗肿瘤的有效方法之一。传统化疗药物的作用机制主要是阻止脱氧核糖核酸(DNA)、核糖核酸(RNA)或蛋白质的合成，或直接对这些大分子发生作用，从而抑制肿瘤细胞的分裂增殖，使之死亡。有些药物也可以通过改变体内激素平衡而抑制肿瘤生长。目前抗肿瘤药物已发展到6大类：①抗代谢药；②烷化剂；③细胞毒素类抗生素；④植物生物碱和其他天然药；⑤抗肿瘤激素类；⑥铂类及其他抗肿瘤药。随着临床治疗模式的转变和一些新的抗肿瘤药物靶点的发现，抗肿瘤药物领域的研发发生了巨大变化：就药物的作用机制而言，从传统的非特异性的细胞毒类药物转向了非细胞毒类 的靶向药物开发。2012年FDA批准的抗肿瘤药物中，小分子酪氨酸激酶抑制剂(TKI)成为研发最热门的一类抗肿瘤药物，尤其是作用于多个靶点的TKI(约占3/4)，截至2013年6月美国FDA批准的TKI已达18种。此外，其他热点作用机制药物包括免疫刺激剂、血管生成抑制剂、细胞周期抑制剂、免疫抑制剂和刺激剂、蛋白激酶抑制剂等。
在感染的哺乳动物细胞中微生物和病毒DNA能通过刺激干扰素分泌诱导內源强有力的免疫应答。内质网(ER)受体蛋白(STING)对胞质DNA的免疫应答是必需的因素。最近的研究表明，环化cGMP-AMP二核苷酸合成酶(cGAS)在结合DNA后的活化条件下，内源性地催化cGAMP的合成。cGAMP是一种胞质DNA传感器，它作为第二信使通过STING刺激INF-β的感应，介导TBK1和IRF-3的活化，进而启动INF-β基因的转录。最近报道，重组cGAS在DNA结合条件下催化环化cGMP-AMP二核苷酸GAMP。cGAS结合18bpdsDNA的复合物的晶体结构也已被报道，cGAMP在抗病毒免疫方面的研究已被证实。cGAMP结合STING，使转录因子IRF3激活并产生β干扰素。
发明内容
本发明的目的在于提供cGAMP在抗肿瘤中的应用。
本发明的目的还在于提出cGAMP在制备抗肿瘤药物中的应用，以制备毒性低、效果好的抗肿瘤药物。
本发明实验研究表明，cGAMP可以抑制多种肿瘤细胞的生长，具有明显的抗肿瘤作用，可用于制备抗肿瘤药物。
本发明中，所述肿瘤包括但不限于胃癌，肺癌，结肠癌，肝癌，前列腺癌，胰腺癌等。
本发明还涉及利用cGAMP所制备的抗肿瘤药。所制备的抗肿瘤药物毒性低、效果好。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中，以下所述的实施例是为了更好地阐述本发明，并不是用来限制本发明的范围。
实施例1：cGAMP的制备
cGAMP(环化-GMP-AMP)按文献方法在结合DNA后的活化条件下，由环化cGMP-AMP二核苷酸合成酶(cGAS)催化合成。纯度在98％以上。(PingweiLi，et al.,Immunity,2013,39(6),1019-1031.)
实施例2：cGAMP(环化-GMP-AMP)的抗肿瘤作用采用荷瘤鼠模型进行检测cGAMP对动物皮下移植瘤生长的抑制作用。
受试药物
名称：cGAMP
性状：白色粉末
溶媒：生理盐水。
配制方法：临用前用生理盐水溶液配制成所需浓度的溶液。
受试药物浓度：1mg/ml、4mg/ml。
动物
种属、品系、性别、体重、来源、合格证
BALB/c裸鼠，雄性，体重16-18g，4-6周龄，SPF级，购于上海斯莱克实验动物有限责任公司[实验动物质量合格证号：SCXK(沪)2007-0005]。
饲养条件
所有裸鼠，均自由觅食和饮水，在室温(23±2)℃，饲养于中国人民解放军某军医大学实验动物中心。饲料及水均经高压灭菌处理，全部实验饲养过程为SPF级。
剂量设置
cGAMP腹腔注射小鼠，设置2个剂量组：10mg/kg，40mg/kg
试验对照
阴性对照：生理盐水溶液
阳性对照：5-氟尿嘧啶(5-FU)，剂量20mg/kg
给药方法
给药途径：腹腔注射给药
给药体积：10ml/kg
给药次数：每天1次，连续14天
每组动物数：8只
肿瘤细胞株
人胃癌细胞株MNK-45，人肺腺癌细胞株A549，人结肠癌细胞株Lovo，人肝癌细胞株SMMC-7721，人前列腺癌细胞株PC-3，人胰腺癌细胞SW1990，均购自中国科学院细胞库。
试验主要步骤
1.荷瘤鼠模型的建立与干预
细胞培养，传代，在细胞对数期收集细胞，做成浓度为1.0×107/ml细胞悬液，裸鼠右前肢腋下注射0.2ml细胞悬液(细胞数目为2.0×106个/只)，10d左右肿瘤长至直径约5mm，致瘤成功，随机均分为4组：阴性对照组(腹腔注射生理盐水组)、5-FU组(腹腔注射5-FU 20mg/kg组)、cGMP-AMP低剂量组(腹腔注射cGMP-AMP)10mg/kg。cGMP-AMP组高剂量组(腹腔注射cGMP-AMP组)40mg/kg。每天给药1次，连续给药14天。14天后，处死裸鼠并称瘤体重量，抑瘤率＝[1-实验组平均瘤重(B、C、D组为实验组)/A组平均瘤重)]×100％。
分别制备6种皮下移植瘤模型：人胃癌细胞株MNK-45，人肺腺癌细胞株 A549，人结肠癌细胞株Lovo，人肝癌细胞株SMMC-7721，人前列腺癌细胞株PC-3，人胰腺癌细胞SW1990，并观察cGAMP的作用。
2.统计分析
数据用x±s表示，利用SPSS10.0软件进行处理，采用单因素方差分析(one-way ANOVA)检验比较各组瘤重差异的显著性，显著性水平a＝0.05。
结果
裸鼠皮下接种肿瘤细胞后制备成功皮下移植瘤模型，5-FU和cGAMP均可明显抑制肿瘤生长，给药14天后的瘤重均显著低于阴性对照组(P<0.05，P<0.01)，表明cGAMP具有抗肿瘤作用。具体结果见表1-表6。
表1cGAMP对裸鼠人胃癌细胞株MNK-45皮下移植瘤的作用
(n＝8，mean±SD)
Figure PCTCN2015076961-appb-000001
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组。
表2cGAMP对裸鼠人肺腺癌细胞株A549皮下移植瘤的作用
(n＝8，mean±SD)
Figure PCTCN2015076961-appb-000002
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组。
表3cGAMP对裸鼠人结肠癌细胞株Lovo皮下移植瘤的作用
(n＝8，mean±SD)
Figure PCTCN2015076961-appb-000003
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组。
表4cGAMP对裸鼠人肝癌细胞株SMMC-7721皮下移植瘤的作用
(n＝8，mean±SD)
Figure PCTCN2015076961-appb-000004
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
表5cGAMP对裸鼠人前列腺癌细胞株PC-3皮下移植瘤的作用
(n＝8，mean±SD)
Figure PCTCN2015076961-appb-000005
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组。
表6cGAMP对裸鼠人胰腺癌细胞SW1990皮下移植瘤的作用
(n＝8，mean±SD)
Figure PCTCN2015076961-appb-000006
注：*P<0.05vs阴性对照组；**P<0.01vs阴性对照组.
实施例3cGAMP的急性毒性研究
实验材料
ICR小鼠20只(购于上海斯莱克实验动物有限责任公司[实验动物质量合格证号：SCXK(沪)2007-0005])，雌雄各半，体重18～22g，动物以颗粒饲料喂养，自由摄食和饮水。
cGAMP由实施例1制备，用生理盐水配制成浓度为200mg/mL的溶液。
实验方法
ICR小鼠按体重单次尾静脉注射10ml/kg的cGAMP即2g/kg，观察给药后小鼠14天内的毒性反应及死亡情况。结果发现，小鼠单次尾静脉注射给药后，小鼠活动正常。给药后14天内，小鼠未出现死亡，第15天，全部小鼠处死，解剖，肉眼检查各脏器，均未见明显病变。
实验结果
上述急性毒性实验结果表明，静脉注射给药最大耐受量MTD不低于2g/Kg，说明cGAMP的急性毒性较低。

Claims (4)

  1. cGAMP在抗肿瘤中的应用。
  2. cGAMP在制备抗肿瘤药物中的应用。
  3. 根据权利要求2所述的cGAMP在制备抗肿瘤药物中的应用，其特征在于，所述肿瘤为胃癌、肺癌、结肠癌、肝癌、前列腺癌或胰腺癌。
  4. 使用cGAMP制备的抗肿瘤药物。
PCT/CN2015/076961 2014-04-21 2015-04-20 环二核苷酸cGAMP在抗肿瘤中的应用 WO2015161762A1 (zh)

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