WO2020215999A1 - 曲氟尿苷或曲氟尿苷替匹嘧啶组合物的医药用途 - Google Patents

曲氟尿苷或曲氟尿苷替匹嘧啶组合物的医药用途 Download PDF

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WO2020215999A1
WO2020215999A1 PCT/CN2020/082054 CN2020082054W WO2020215999A1 WO 2020215999 A1 WO2020215999 A1 WO 2020215999A1 CN 2020082054 W CN2020082054 W CN 2020082054W WO 2020215999 A1 WO2020215999 A1 WO 2020215999A1
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trifluridine
composition
tepipyrimidine
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hbf
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张若文
周德旺
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张若文
周德旺
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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
    • A61K31/495—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
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    • A61K31/7072—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 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

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  • the present invention relates to the technical field of medicine, and relates to the medicinal use of trifluridine or trifluridine tepipyrimidine composition, in particular to the use of trifluridine or trifluridine tepipyrimidine composition in the preparation of drugs for the treatment of blood diseases
  • the application in particular, relates to the application of trifluridine or trifluridine tepipyrimidine composition in the preparation of medicines for treating blood diseases caused by ⁇ -hemoglobin gene defects or gene mutations.
  • Infant and adult hemoglobin is a tetramer composed of 2 alpha chains and 2 gamma chains (infants) or beta chains (adults). They carry oxygen and carbon dioxide in the human body.
  • the molecular structure and synthesis of hemoglobin are determined by genes. Among them, due to the deletion or point mutation of the ⁇ hemoglobin gene, the disorder of ⁇ chain synthesis leads to insufficient hemoglobin production or structural abnormalities, resulting in the inability to effectively carry oxygen and eventually various clinical symptoms. As a result, the life expectancy of these patients was significantly shortened and the quality of life decreased.
  • Blood diseases caused by ⁇ -hemoglobin gene defects or mutations mainly include ⁇ -thalassemia and sickle-type anemia.
  • HbF fetal hemoglobin
  • HbF production pathway is mainly regulated by the expression level of the gene KLF1. Therefore, as long as a drug that can effectively reduce the expression of the KLF1 gene is found, HbF production can be reactivated, so as to achieve the goal of treating blood diseases caused by ⁇ -hemoglobin gene defects or mutations.
  • the inventors independently developed and perfected a set of high-throughput screening system for inducing HbF expression based on the directional differentiation of human hematopoietic stem cells into red blood cells as a model.
  • Trifluridine tepipyridine (TAS-102) is composed of trifluridine and thymidine phosphorylase inhibitor tepipyridine in a weight ratio of 2:1. It is an oral fluorouracil drug. It was approved by the US FDA on September 22, 2015 for the treatment of refractory metastatic colorectal cancer (mCRC) patients who no longer respond to other therapies (chemotherapy and biological therapies), and was approved by Europe in April 2016 Approved by the Drug Administration. Up to now, it has been approved for the treatment of metastatic colorectal cancer (mCRC) in 21 countries and regions including Japan, the United States, the United Kingdom, Canada, and the European Union.
  • mCRC metastatic colorectal cancer
  • the technical problem to be solved by the present invention is to screen the chemical components that can effectively activate the production of HbF in human red blood cells, and to prepare drugs for the treatment of blood diseases caused by ⁇ -hemoglobin gene defects or mutations.
  • the application of the drug can completely cancel the application of iron removal agents, reduce or even replace blood transfusion therapy, reduce the patient's dependence on blood transfusion, and alleviate the current shortage of medical blood sources in the country.
  • the invention provides the medical use of trifluridine or trifluridine tepipyrimidine composition.
  • the present invention provides the application of trifluridine or trifluridine tepipyrimidine composition in the preparation of medicines for treating blood diseases.
  • the present invention provides the application of trifluridine or trifluridine tepipyrimidine in the preparation of medicines for treating blood diseases caused by ⁇ -hemoglobin gene deletion or point mutation.
  • the blood disease is thalassemia or sickle anemia.
  • the weight composition ratio of trifluridine and tepipyridine is 1:1-4:1.
  • a drug screening system that takes the directional differentiation of human hematopoietic stem cells into red blood cells in vitro as a model, and uses KLF1 and HbF gene expression as indicators.
  • a small molecule drug trifluridine or trifluridine tepipyrimidine composition that can reduce the expression of KLF1 gene in red blood cells and significantly increase the expression of HbF is screened out.
  • trifluridine can reduce the expression of KLF1 gene in red blood cells and significantly increase the expression of HbF.
  • Tepipyridine can mainly reduce the degradation rate of trifluridine in the human body.
  • trifluridine and tepipyridine The weight composition ratio of 1:1-4:1 can effectively improve the expression of HbF.
  • Figure 5 PCR method to detect the expression of HbF gene in human red blood cells under the action of drugs.
  • Example 1 PCR method to detect the expression of the target gene in human red blood cells under the action of drugs
  • PCR primer information is as follows
  • trifluridine tepipyrimidine can reduce the gene expression of KLF1 and BCL11A in the body, while the control drug hydroxyurea cannot reduce the expression of the target gene.
  • trifluridine tepipyrimidine can significantly increase the expression of HbF gene in human red blood cells, while hydroxyurea only slightly increases the expression of HbF gene.
  • the dosage of hydroxyurea is 10 ⁇ M, while the dosage of 0.15 ⁇ M of trifluridine tepipyridine is only 1.5% of the dosage of hydroxyurea. Under this dosage, trifluridine tepipyrimidine can increase the expression of HbF gene by three times the effect of hydroxyurea.
  • Example 2 Flow cytometry to detect HbF protein expression in human red blood cells under the action of drugs
  • the cell culture method is as described in Example 1.
  • the cells were cultured for 14 days, washed with pBS containing 0.1% BSA, and fixed with 0.05% glutaraldehyde (Sigma, G5882).
  • the fixed cells were washed 3 times with pBS containing 0.1% BSA, then permeabilized in 1% Triton X-100 (Life Technologies, HFH-10), and then immunostained with an antibody against HbF (Invitrogen, MHFH04).
  • the cells after immunostaining were analyzed by flow cytometry, and the results are shown in Figure 3.
  • Example 3 Western immunoblotting method to detect the protein expression of HbF in human red blood cells under the action of drugs
  • the cell culture method is as described in Example 1.
  • the cells were cultured for 14 days and washed with pBS containing 0.1% BSA.
  • the cells were then lysed in 1% Triton X-100 (Life Technologies, HHF-10), and the supernatant was centrifuged.
  • the protein lysate was quantified, added to the protein loading buffer, separated by SDS polyacrylamide gel electrophoresis, and then transferred to the vinylidene fluoride membrane (PVDF) by electrophoretic imprinting, using anti-HbF antibody (Abcam) and Anti- ⁇ -actin (Cellsignaling) antibody labeling, HRP coupled with secondary antibody labeling (Cellsingaling) followed by electrochemiluminescence immunochromatography, the results are shown in Figure 4.
  • PVDF vinylidene fluoride membrane
  • trifluridine tipicil is more effective than hydroxyurea in increasing the expression of HbF in human red blood cells, and the dosage of trifluridine tipicil is only 1.5% of the dosage of hydroxyurea.
  • Trifluridine tepipyrimidine (TAS-102) is composed of tetrafluridine and thymidine phosphorylase inhibitor tepipyridine in a weight ratio of 2:1.
  • the composition of :1 can increase the expression of HbF in human red blood cells, and can ensure its efficacy in treating blood diseases caused by ⁇ -hemoglobin gene defects or mutations.
  • trifluridine or fluridine tepipyrimidine can be used to prepare drugs for effective treatment of blood diseases caused by ⁇ -hemoglobin gene defects or mutations.

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Abstract

曲氟尿苷或曲氟尿苷替匹嘧啶组合物在制备治疗血液疾病药物中的应用，具体涉及在制备治疗β血红蛋白基因缺损或基因突变导致的血液疾病的药物中的应用。曲氟尿苷替匹嘧啶组合物由曲氟尿苷和替匹嘧啶组成，其重量组成比为：1:1-4:1，所述组合物还可以和药学上可接受的载体制备成药物组合物用于制备治疗血液疾病的药物。

Description

曲氟尿苷或曲氟尿苷替匹嘧啶组合物的医药用途 技术领域
本发明涉及医药技术领域，涉及曲氟尿苷或曲氟尿苷替匹嘧啶组合物的医药用途，具体涉及曲氟尿苷或曲氟尿苷替匹嘧啶组合物在制备治疗血液疾病药物中的应用，尤其涉及曲氟尿苷或曲氟尿苷替匹嘧啶组合物在制备治疗β血红蛋白基因缺损或基因突变导致的血液疾病的药物中的应用。
背景技术
婴儿和成年人血红蛋白是由2条α链和2条γ链(婴儿)或β链(成年)组成的四聚体。它们在人体内运载氧气和二氧化碳。血红蛋白的分子结构及合成是由基因决定的，其中由于β血红蛋白基因的缺失或点突变，β链合成障碍导致血红蛋白生成不足或结构异常，致使无法有效地携带氧气最终出现各种程度的临床症状，导致这些病人的寿命明显缩短,生活质量下降。β血红蛋白基因缺损或突变导致的血液疾病主要包括β型地中海贫血和镰刀型贫血病等。β血红蛋白异常导致的疾病严重程度与患者胎儿血红蛋白(HbF)含量密切相关。如果病人体内HbF生成途径未完全关闭,则临床症状较轻,生存期明显延长。提高地贫患者HbF水平到20％以上的水平，可以明显缓解HbA不足的缺陷，达到治疗病人血红蛋白生成不足的目的。理论上，人体HbF生成途径在出生一年后基本处于关闭状态，医药研发机构尚未找到任何有效重新激活HbF生成的药物。目前全世界唯一可用于临床缓解β型地中海贫血症状的药物是羟基脲(Hydroxyurea)，但该药治疗机理不明，临床治疗剂量高，效果不明显，患者用药后有包括影响生殖的严重副反应的风险。
经过我们多年的研究发现，人体HbF生成途径主要受基因KLF1的表达水平调控。因此只要找到可以有效降低KLF1基因表达的药物，就可以重新激活HbF生成，从而达到治疗β血红蛋白基因缺损或突变导致的血液疾病的目的。基于此理论基础，发明人自行开发 并完善了一套以人体造血干细胞体外定向分化成红细胞为模型，针对诱导HbF表达的高通量筛选系统。
曲氟尿苷替匹嘧啶(TAS-102)由曲氟尿苷和胸腺嘧啶磷酸化酶抑制剂替匹嘧啶以重量比2：1组成，为口服的氟尿嘧啶类药物。于2015年9月22日获美国FDA批准，用于对其他疗法(化疗及生物疗法)不再响应的难治性转移性结直肠癌(mCRC)患者的治疗，并在2016年4月由欧洲药品管理局批准。截至目前，已在日本、美国、英国、加拿大、欧盟等21个国家和地区获批用于治疗转移性结直肠癌(mCRC)。并且，由于高级别的循证证据和良好的临床使用感受，已被列入《NCCN结直肠临床实践指南》、《ESMO转移性结直肠癌患者管理共识》、《JSCCR(日本结直肠癌学会)结直肠癌治疗指南》，推荐曲氟尿苷替匹嘧啶用于既往接受过含氟嘧啶、奥沙利铂和伊立替康化疗和靶向治疗的转移性结直肠癌患者(mCRC)。临床上仅用于癌症的治疗，此前完全没有在制备治疗血液疾病药物中应用的相关报道。
发明内容
针对现有技术的不足，本发明要解决的技术问题是筛选可有效地激活人体红细胞中HbF生成的化学组分，用于制备治疗β血红蛋白基因缺损或突变导致的血液疾病的药物，以此建立全新的药物治疗β血红蛋白基因缺损或突变导致的血液疾病的方法。该药物的应用完全可以取消去铁剂的应用，减少甚至取代输血治疗，降低患者对输血的依赖程度，缓解国家医用血源紧缺的现状。
本发明通过如下技术方案实现：
本发明提供了曲氟尿苷或曲氟尿苷替匹嘧啶组合物的医药用途。
进一步地，本发明提供了曲氟尿苷或曲氟尿苷替匹嘧啶组合物在制备治疗血液疾病的药物中的应用。
更进一步地，本发明提供了曲氟尿苷或曲氟尿苷替匹嘧啶在制备治疗β血红蛋白基因缺失或点突变导致的血液疾病药物中的应用。
优选地，所述的血液疾病为地中海型贫血或镰刀型贫血。
本发明中，所述的曲氟尿苷替匹嘧啶组合物中，曲氟尿苷和替匹嘧啶的重量组成比为：1:1-4:1。
本发明中，提供了以人体造血干细胞体外定向分化成红细胞为模型，以KLF1，HbF基因表达量为指标的药物筛选系统。通过此系统筛选出一种能降低红细胞内KLF1基因表达，显著提高HbF表达的小分子药物曲氟尿苷或曲氟尿苷替匹嘧啶组合物。
试验结果表明，曲氟尿苷能降低红细胞内KLF1基因表达，显著提高HbF的表达，替匹嘧啶主要是能降低曲氟尿苷在人体内降解的速度，其中，曲氟尿苷和替匹嘧啶的重量组成比为：1:1-4:1的组合物均可有效提高HbF的表达。
附图说明
图1PCR法检测药物作用下KLF1和BCL11A基因在人红细胞中的表达量；(曲氟尿苷：替匹嘧啶＝2：1)
图2PCR法检测药物作用下HbF基因在人红细胞中的表达量；(曲氟尿苷：替匹嘧啶＝2：1)
图3流式细胞法检测HbF在药物作用下在人红细胞中的蛋白表达量；(曲氟尿苷：替匹嘧啶＝2：1)
图4Western免疫印记法检测HbF在药物作用下在人红细胞中的蛋白表达量；(曲氟尿苷：替匹嘧啶＝2：1)
图5PCR法检测药物作用下HbF基因在人红细胞中的表达量。
具体实施方式
实施例1PCR法检测目的基因在药物作用下在人红细胞中的表达量
将5x10 5个CD34 +细胞在含有细胞因子SCF(Stem cell factor)，IL-3(Interleukin 3)，TPO(Thrombopoietin)和Flt-3L(Fms-like tyrosine kinase 3 ligand)的StemSpan SFEM培养液(StemCell Technologies Inc.)中培养。6天后，将1x10 5个细胞分配到每个孔(24孔板)中，并在含有2％青/链霉素，20ng/ml SCF，1U/ml Epo，5ng/ml IL-3,2uM地塞米松和1uMβ-雌二醇的SFEM培养液中生长。从第一天开始向每个孔中加入小分子药物，每两天换一次培养液并加入新的小分子药物。细胞培养9天后，利用mRNA提取试剂盒(Invitrogen)提取细胞中的mRNA，用反转录试剂盒通(Applied Biosystem)建立cDNA文库，最终通过PCR法分析每个样品中的目的基因在人红细胞中的表达量结果见图1，图2和图5。
PCR法引物信息如下
Human GAPDH(内参):Forward 5’-GTGAAGGTCGGAGTCAACG-3’Reverse 5’-
TGAGGTCAATGAAGGGGTC-3’
Human KLF1:Forward 5’-CCACAGCCGAGACCGCCTTGACC-3’Reverse 5’-
CTCTCATCGTCCTCTTCCTCCC-3’
Human BCL11A:Forward 5’-CGAGCACAAACGGAAACAATG-3’Reverse 5’-
GATTAGAGCTCCATGTGCAGAACG-3’
Humanγ-globin(HbF):Forward 5’-GATGCCATAAAGCACCTGGATG-3’Reverse 5’-
TTGCAGAATAAAGCCTATCCTTGA-3’
Humanβ-globin(HbA):Forward 5’-AACTGTGTTCACTAGCAACCTCAA-3’Reverse 5’-
GAGTGGACAGATCCCCAAAGGA-3’。
根据图1所示曲氟尿苷替匹嘧啶能降低体内KLF1和BCL11A的基因表达，对照药物羟基脲不能降低目的基因表达。
根据图2所示，曲氟尿苷替匹嘧啶能明显提高人红细胞内HbF基因的表达，而羟基脲仅略微提高HbF基因的表达。羟基脲的用量为10μM，而曲氟尿苷替匹嘧啶的用量0.15μM仅为羟基脲用量的1.5％。在此用量下，曲氟尿苷替匹嘧啶可以提高HbF基因表达三倍于羟基脲的效果。
根据图5所示，单独使用曲氟尿苷或者将曲氟尿苷和替匹嘧啶以不同比例组成(1：1-4：1)都可以显著地提高HbF基因在人红细胞中的表达，药效并无明显差异，说明在人红细胞中，提高HbF表达的主要成分为曲氟尿苷。
实施例2：流式细胞法检测药物作用下HbF在人红细胞中的蛋白表达量
细胞培养方法如实施例1所述。细胞培养14天，用含有0.1％BSA的pBS洗涤，并用0.05％戊二醛(Sigma，G5882)固定细胞。将固定的细胞用含有0.1％BSA的pBS洗涤3次，然后在1％Triton X-100(Life Technologies，HFH-10)中透化，随后用针对HbF的抗体(Invitrogen，MHFH04)进行免疫染色。免疫染色后的细胞再进行流式细胞仪分析，结果见图3。
根据图3所示，在曲氟尿苷替匹嘧啶作用下，HbF的信号峰明显右移，提示人红细胞中的HbF蛋白表达量明显增高。
实施例3：Western免疫印记法检测HbF在药物作用下在人红细胞中的蛋白表达量
细胞培养方法如实施例1所述。细胞培养14天，用含有0.1％BSA的pBS洗涤，细胞然后在1％Triton X-100(Life Technologies，HFH-10)中裂解，离心取上清液。将蛋白裂解液定量，加入蛋白上样缓冲液，经SDS聚炳烯酰胺凝胶电泳分离，之后用电泳印记法将蛋白转移到偏二氟乙烯膜(PVDF)，用抗HbF抗体(Abcam)和抗β-actin(Cellsignaling)抗体标记，HRP偶联二抗标记(Cellsingaling)后进行电化学发光免疫显色，结果见图4。
根据图4所示，相较于羟基脲的作用，HbF蛋白水平在曲氟尿苷替匹嘧啶作用下明显升高，以β-acitn蛋白水平为蛋白上样量内参。
综上所述，曲氟尿苷替匹嘧啶比羟基脲更有效的提高HbF在人红细胞中的表达，而且曲氟尿苷替匹嘧啶的使用剂量仅为羟基脲的用量的1.5％。
曲氟尿苷替匹嘧啶(TAS-102)由曲氟尿苷和胸腺嘧啶磷酸化酶抑制剂替匹嘧啶以重量比2：1组成。本发明经过试验发现，曲氟尿苷替匹嘧啶(TAS-102)能够明显提高HbF 在人红细胞中的表达，而改变其重量组成得到的曲氟尿苷：替匹嘧啶＝1：1-4：1的组合物，均可以提高HbF在人红细胞中的表达，均可以保证其治疗β血红蛋白基因缺损或突变导致的血液疾病的药效。
综上所述，曲氟尿苷或氟尿苷替匹嘧啶可以用于制备有效治疗β血红蛋白基因缺损或突变导致的血液疾病的药物。

Claims (10)

  1. 曲氟尿苷在制备治疗血液疾病药物中的应用。
  2. 曲氟尿苷在制备治疗β血红蛋白基因缺失或点突变导致的血液疾病药物中的应用。
  3. 曲氟尿苷替匹嘧啶组合物在制备治疗血液疾病药物中的应用。
  4. 曲氟尿苷替匹嘧啶组合物在制备治疗β血红蛋白基因缺失或点突变导致的血液疾病药物中的应用。
  5. 如权利要求1-4所述的应用，其特征在于，所述的血液疾病为地中海型贫血或镰刀型贫血。
  6. 如权利要求1-4任何一项所述的应用，其特征在于，所述的曲氟尿苷或曲氟尿苷替匹嘧啶组合物通过降低红细胞中基因KLF1的表达来提高胎儿血红蛋白的表达，进而改善或治愈β血红蛋白异常导致的血液疾病。
  7. 如权利要求1-4任何一项所述的应用，其特征在于，所述的曲氟尿苷替匹嘧啶组合物由曲氟尿苷和替匹嘧啶组成，其重量比为：1:1-4:1。
  8. 如权利要求1-5任何一项所述的应用，其特征在于，所述的曲氟尿苷或曲氟尿苷替匹嘧啶组合物和药学上可接受的载体制备成药物组合物。
  9. 如权利要求1-5任何一项所述的应用，其特征在于，所述的曲氟尿苷或曲氟尿苷替匹嘧啶组合物与药学上可接受的载体制备成临床上可接受的制剂。
  10. 如权利要求9所述的应用，其特征在于，所述的制剂为片剂、胶囊、颗粒剂或注射针剂。
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