WO2022111390A1 - 化合物在制备调降 runx2 表达试剂中的应用 - Google Patents

化合物在制备调降 runx2 表达试剂中的应用 Download PDF

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WO2022111390A1
WO2022111390A1 PCT/CN2021/131753 CN2021131753W WO2022111390A1 WO 2022111390 A1 WO2022111390 A1 WO 2022111390A1 CN 2021131753 W CN2021131753 W CN 2021131753W WO 2022111390 A1 WO2022111390 A1 WO 2022111390A1
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acid
acceptable salts
runx2
tumor
sulfonic
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French (fr)
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潘武广
朱威
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广州君赫生物科技有限公司
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Priority to CN202180076319.0A priority Critical patent/CN116635030A/zh
Priority to EP21896891.5A priority patent/EP4233866A1/en
Publication of WO2022111390A1 publication Critical patent/WO2022111390A1/zh
Priority to US18/200,591 priority patent/US20230288401A1/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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

Definitions

  • the present invention relates to new applications of the compounds, in particular to the application of the compounds in the preparation of reagents for regulating the expression of RUNX2, anti-tumor drugs and the like.
  • Runx2 is a well-established transcription factor that plays an important role in the transformation of bone marrow mesenchymal stem cells into osteoblasts. In vitro and in vivo studies have shown that it can participate in bone metabolism, ectopic calcification of the cardiovascular system, abnormal tooth development, tumors and organs through various signal transduction pathways such as bone morphogenetic proteins/Smads and mitogen-activated protein kinase signaling pathways. fibrosis and other diseases. The specific mechanism of Runx2 in the occurrence, development and prognosis of the disease has not been fully clarified, and the treatment of clinical diseases with Runx2 as the target may become a research hotspot.
  • Runx2 is highly expressed in a variety of tumors, such as breast cancer, lung cancer, lung adenocarcinoma, prostate cancer, multiple myeloma, and malignant phyllodes tumor of the breast, which directly affects tumor progression.
  • Tumors seriously endanger people's health, and different tumors have different responses to the same drug.
  • it has become a consensus of tumor treatment to formulate a reasonable drug regimen based on the phenotype of the tumor.
  • Fostamatinib is a prodrug of R406, the active metabolite of spleen tyrosine kinase (SYK) inhibitor, DrugBankID: DB12010, CAS number: 945745-48-2, with a variety of medical therapeutic effects, by the United States Rigel Developed by a pharmaceutical company for the treatment of thrombocytopenia, particularly in adult patients with chronic immune thrombocytopenia (ITP) who have not responded well to previous treatment regimens.
  • SYK spleen tyrosine kinase
  • Regorafenib (Regorafenib), DrugBankID: DB08896, CAS No: 755037-03-7, is a small-molecule inhibitor of various membrane-bound intracellular kinases that are involved in normal cellular functions and pathological processes, such as tumorigenesis , tumor angiogenesis is associated with the maintenance of the tumor microenvironment.
  • regorafenib or its major human active metabolites M-2 and M-5 inhibit RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2 , at regorafenib concentrations reached clinically achieved DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5 and Abl.
  • regorafenib has shown antiangiogenic activity in rat tumor models and inhibition of tumor growth as well as anti-tumor activity in several mouse xenograft models, including some human colorectal cancers. transfer activity.
  • Regorafenib has relatively large side effects, and its approved clinical use is for the treatment of patients who have received fluorouracil, oxaliplatin, and irinotecan-based chemotherapy, and who have received or are not suitable for anti-VEGF therapy, anti-EGFR therapy (RAS wild-type) metastatic colorectal cancer; for the treatment of locally advanced, unresectable, or metastatic gastrointestinal stromal tumors previously treated with imatinib mesylate and sunitinib malate patients; for the treatment of hepatocellular carcinoma previously treated with sorafenib.
  • RAS wild-type metastatic colorectal cancer
  • Melatonin (Melatonin, MT) is one of the hormones secreted by the brain pineal gland, DrugBankID: DB01065, CAS number: 73-31-4. Also known as pineal hormone, melatonin, melatonin. MT has strong neuroendocrine immunomodulatory activity and free radical scavenging antioxidant capacity.
  • a first aspect of the present invention provides:
  • compositions in the preparation of a reagent for regulating Runx2 expression wherein the active ingredient of the composition is at least selected from Fostamatinib and its acceptable salts, Regorafenib and its acceptable salts, and melatonin and its acceptable salts. A sort of.
  • the salt is an acid or base addition salt of the compound.
  • the acid is selected from acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (eg, L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4 -Acetaminobenzoic acid, butyric acid, (+)camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cycloheximide Lauric acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-isethionic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptose acid, D-gluconic acid, glucuronic acid (such as D-glucuronic acid (
  • the application is experimental.
  • a second aspect of the present invention provides:
  • composition is used in the preparation of antitumor drugs, and the active ingredients of the composition include at least one of Fostamatinib and its acceptable salts, Regorafenib and its acceptable salts, and melatonin and its acceptable salts, at least 2, at least 3.
  • the tumor is a tumor indicative of high Runx2 expression.
  • the tumor is selected from breast cancer, lung cancer, lung adenocarcinoma, prostate cancer, multiple myeloma, malignant phyllodes tumor of the breast.
  • the composition further includes at least one active ingredient known to have therapeutic effects on tumors.
  • the salt is an acid or base addition salt of the compound.
  • the acid is selected from acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (eg, L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4 -Acetaminobenzoic acid, butyric acid, (+)camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cycloheximide Lauric acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-isethionic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptose acid, D-gluconic acid, glucuronic acid (such as D-glucuronic acid (
  • a third aspect of the present invention provides:
  • a method of targeting a tumor comprising:
  • a therapeutic amount of a composition comprising at least one of the active ingredients of Fostamatinib and acceptable salts thereof, Regorafenib and acceptable salts thereof, and melatonin and acceptable salts thereof is administered A sort of.
  • high Runx2 expression is defined as a relatively significantly higher level of expression compared to normal tissue, such as 1.5-fold, 2-fold, 3-fold, 5-fold or more higher than that in normal tissue.
  • administration of an active ingredient known to have a therapeutic effect on a tumor is also included.
  • the salt is an acid or base addition salt of the compound.
  • the acid is selected from acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (eg, L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4 -Acetaminobenzoic acid, butyric acid, (+)camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cycloheximide Lauric acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-isethionic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptose acid, D-gluconic acid, glucuronic acid (such as D-glucuronic acid (
  • Fostamatinib, Regorafenib and melatonin can significantly down-regulate the expression of Runx2, and have significant targeted therapeutic effects on cancers with abnormally high Runx2 expression. drop reagent.
  • Fostamatinib, Regorafenib, and melatonin can effectively improve efficacy and/or reduce side effects.
  • Fostamatinib, Regorafenib and Melatonin can produce the same or similar effects as Fostamatinib, Regorafenib and Melatonin in vivo or in a cellular environment, and also have corresponding therapeutic effects or effects.
  • Figure 1 is the expression level of RUNX2 protein after Fostamatinib acts on lung cancer cell A549 and lung cancer cell H1299 for 8h respectively;
  • Figure 2 is the expression level of RUNX2 mRNA after Fostamatinib acts on lung cancer cell A549 and lung cancer cell H1299 for 8h respectively;
  • Figure 3 is the expression level of RUNX2 protein after Fostamatinib acts on lung cancer cell A549 and lung cancer cell H1299 for 6h respectively;
  • Figure 4 is the expression level of RUNX2 mRNA after Fostamatinib acts on lung cancer cell A549 and lung cancer cell H1299 for 6h respectively;
  • Figure 5 is the expression level of RUNX2 protein after treatment of different concentrations of Fostamatinib in BEL-7402 liver cancer cells for 6h;
  • Figure 6 is the effect of intraperitoneal injection of fostamatinib on the expression level of RUNX2 mRNA in mice.
  • the expression level is relatively significantly increased compared with normal tissues. In general, its expression level is 1.5 times, 2 times, 3 times, 5 times or more than in normal tissues. .
  • salts of compounds can be synthesized from the parent compound by conventional chemical methods, as described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: The method described in 3-90639-026-8, Hardcover, 388 pages, August 2002.
  • these salts can be prepared by reacting the free base of the compound with an acid in water or an organic solvent or a mixture of the two; usually, using a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile .
  • Acid addition salts can be prepared from a variety of acids (inorganic and organic).
  • acid addition salts include salts made from acids selected from acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (eg L-ascorbic acid), L-aspartic acid , benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+)camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, Caprylic acid, cinnamic acid, citric acid, cyclonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-isethionic acid, formic acid, fumaric acid, galactose acid, gentisic acid, glucoheptonic acid, D
  • the inventors confirmed through computational studies and preliminary experimental studies on relevant disease models:
  • Fostamatinib, Regorafenib and melatonin can significantly down-regulate the expression of Runx2, and have significant targeted therapeutic effects on cancers with abnormally high Runx2 expression. drop reagent.
  • Fostamatinib, Regorafenib and Melatonin can produce the same or similar effects as Fostamatinib, Regorafenib and Melatonin in vivo or in a cellular environment, and also have corresponding therapeutic effects or effects.
  • the cells were seeded in medium-sized dishes (6cm) and cultured overnight. When the cell confluence was 80%, the original medium was discarded. After rinsing the cells with PBS, they were replaced with Fostamatinib containing a final concentration of 10uM or other concentrations. After ⁇ 12 hours, cells were harvested, RNA and protein solution were extracted, and the protein and mRNA expression changes of RUNX2 were detected by Western blot and qPCR experiments, respectively.
  • Figure 1 shows that after Fostamatinib acts on lung cancer cells A549 and lung cancer cells H12998h respectively, the expression level of RUNX2 protein has a downward trend (in the figure, F represents Fostamatinib).
  • Figure 2 shows that the mRNA level of RUNX2 was significantly decreased after Fostamatinib acted on lung cancer cell A549 and lung cancer cell H1299 for 8 h, respectively.
  • Figure 3 shows that after Fostamatinib acts on lung cancer cells A549 and lung cancer cells H1299 for 6 h, the expression level of RUNX2 protein has a certain downward trend (in the figure, F represents Fostamatinib, the antibody has been replaced).
  • Figure 4 shows that the mRNA level of RUNX2 was significantly decreased after Fostamatinib acted on lung cancer cell A549 and lung cancer cell H1299 for 6 h, respectively.
  • Figure 5 shows that after treating liver cancer cells BEL-7402 with 0, 2.5, 5, and 10 uM of Fostamatinib for 6 h, the protein levels of liver cancer cells were significantly decreased in a dose-dependent manner.
  • mice 8-week-old C57BL/6 male mice
  • mice were randomly divided into two groups, the experimental group (fostamatinib) and the control group (mock). Before the experiment, a certain amount of fostamatinib was accurately weighed and dissolved in 0.5% CMC (nitromethylcellulose). Fully blow and beat evenly to obtain a homogeneous suspension, the concentration of preparation is 4mg/ml, and it is used and prepared now. According to the injection volume of 100ul/10g per mouse, intraperitoneal injection was carried out for 4 consecutive days. The mouse liver tissue was taken 48 hours after the last injection, RNA was extracted, and the mRNA expression of RUNX2 was detected by real-time quantitative PCR (qPCR) method. Level. The experiment is shown in Figure 6. It can be seen that fostamatinib can significantly reduce the mRNA expression level of RUNX2 and has an anti-tumor effect.
  • CMC nitromethylcellulose

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Abstract

化合物在制备调降Runx2表达试剂中的应用。经过模型证实，Fostamatinib、Regorafenib和褪黑素均可以显著下调Runx2的表达量，可用于Runx2高表达癌症的靶向治疗或实验用试剂。

Description

化合物在制备调降RUNX2表达试剂中的应用 技术领域
本发明涉及化合物的新应用，特别涉及化合物在制备调降RUNX2表达试剂、抗肿瘤药物等中的应用。
 背景技术
Runx2是一种公认的转录因子，对骨髓间充质干细胞向成骨细胞转化的过程起重要作用。体内外的研究表明，它可通过骨形态发生蛋白/Smads、丝裂原活化蛋白激酶信号通路等多种信号转导途径参与骨代谢，心血管***的异位钙化，牙齿异常发育，肿瘤和器官纤维化等疾病的发生。Runx2在疾病的发生、发展以及预后的具体作用机制尚未完全明确，以Runx2为靶点治疗临床疾病或将成为研究热点。已有研究表明Runx2在多种肿瘤，如乳腺癌、肺癌、肺腺癌、***癌、多发性骨髓瘤、乳腺恶性叶状肿瘤中高表达，直接影响肿瘤的进展。
肿瘤严重危害人们的身体健康，同时不同的肿瘤对同一药物也具有不同的反应。为提高疗效，减少副作用，基于肿瘤的表型，制订合理的用药方案，已经成为肿瘤治疗的共识。
福坦替尼(fostamatinib)是脾脏酪氨酸激酶(SYK)抑制药的活性代谢产物R406的前体药物，DrugBankID：DB12010，CAS号：945745-48-2，具有多种医学治疗作用，由美国Rigel 制药公司开发，用于血小板减少症的治疗，特别是对此前治疗方案缓解不佳的成年慢性免疫性血小板减少症(ITP)患者。
Regorafenib(瑞戈菲尼)，DrugBankID：DB08896，CAS号：755037-03-7，是多种与细胞膜结合的胞内激酶的小分子抑制剂，这些激酶与正常细胞功能和病理过程，例如肿瘤发生，肿瘤血管生成和肿瘤微环境的维持相关。在体外生化或细胞分析中，雷戈非尼或其主要人类活性代谢产物M-2和M-5抑制RET，VEGFR1，VEGFR2，VEGFR3，KIT，PDGFR-alpha，PDGFR-beta，FGFR1，FGFR2，TIE2，在regorafenib浓度达到临床上已达到的DDR2，TrkA，Eph2A，RAF-1，BRAF，BRAFV600E，SAPK2，PTK5和Abl。在体内模型中，雷戈非尼在大鼠肿瘤模型中显示出抗血管生成活性，并在几种小鼠异种移植模型（包括某些人结肠直肠癌）中显示出对肿瘤生长的抑制以及抗转移活性。Regorafenib的副作用比较大，已批准的临床用途为用于治疗既往接受过氟尿嘧啶、奥沙利铂和伊立替康为基础的化疗，以及既往接受过或不适合接受抗VEGF治疗、抗EGFR治疗（RAS野生型）的转移性结直肠癌患者；用于治疗既往接受过甲磺酸伊马替尼及苹果酸舒尼替尼治疗的局部晚期的、无法手术切除的或转移性的胃肠间质瘤患者；用于治疗既往接受过索拉非尼治疗的肝细胞肝癌。
褪黑素（Melatonin，MT）是由脑松果体分泌的激素之一，DrugBankID：DB01065，CAS号：73-31-4。又称为松果体素、褪黑激素、褪黑色素。MT有强大的神经内分泌免疫调节活性和清除自由基抗氧化能力。
 技术问题
开发已有化合物的新应用，具有非常重要的意义。
 技术解决方案
本发明所采取的技术方案是：
本发明的第一个方面，提供：
组合物在制备调降Runx2表达试剂中的应用，所述组合物的活性成分选自Fostamatinib及其可接受的盐、Regorafenib及其可接受的盐和褪黑素及其可接受的盐中的至少一种。
在一些实例中，所述盐为化合物的酸或碱加成盐。
在一些实例中，所述酸选自由乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸（如L-抗坏血酸）、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、（+）樟脑酸、樟脑-磺酸、（+）-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸（如D-葡萄糖醛酸）、谷氨酸（如L-谷氨酸）、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、（+）-L-乳酸、（±）-DL-乳酸、乳糖酸、马来酸、苹果酸、（-）-L-苹果酸、丙二酸、（±）-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、（+）-L-酒石酸、硫氰酸、 p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸组成的组；所述碱为碱金属、碱土金属的氢氧化物。
在一些实例中，所述应用为实验用。
本发明的第二个方面，提供：
组合物在制备抗肿瘤药物中应用，所述组合物的活性成分包括Fostamatinib及其可接受的盐、Regorafenib及其可接受的盐和褪黑素及其可接受的盐中的至少一种，至少2种、至少3种。
在一些实例中，所述肿瘤为具有Runx2高表达指征的肿瘤。
在一些实例中，所述肿瘤选自乳腺癌、肺癌、肺腺癌、***癌、多发性骨髓瘤、乳腺恶性叶状肿瘤。
在一些实例中，所述组合物还包括至少一种对肿瘤具有治疗作用的已知活性成分。
在一些实例中，所述盐为化合物的酸或碱加成盐。
在一些实例中，所述酸选自由乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸（如L-抗坏血酸）、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、（+）樟脑酸、樟脑-磺酸、（+）-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸（如D-葡萄糖醛酸）、谷氨酸（如L-谷氨酸）、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、（+）-L-乳酸、（±）-DL-乳酸、乳糖酸、马来酸、苹果酸、（-）-L-苹果酸、丙二酸、（±）-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、（+）-L-酒石酸、硫氰酸、 p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸组成的组；所述碱为碱金属、碱土金属的氢氧化物。
本发明的第三个方面，提供：
一种靶向***的方法，包括：
对肿瘤患者的样品进行检测，确定Runx2是否高表达；
针对Runx2高表达的患者，给予治疗量的组合物，所述组合物的活性成分包括Fostamatinib及其可接受的盐、Regorafenib及其可接受的盐和褪黑素及其可接受的盐中的至少一种。
在一些实例中，Runx2高表达定义为与正常组织相比，其表达量相对显著高，如高于正常组织表达量的1.5倍、2倍、3倍、5倍或更多。
在一些实例中，还包括给予一种对肿瘤具有治疗作用的已知活性成分。
在一些实例中，所述盐为化合物的酸或碱加成盐。
在一些实例中，所述酸选自由乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸（如L-抗坏血酸）、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、（+）樟脑酸、樟脑-磺酸、（+）-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸（如D-葡萄糖醛酸）、谷氨酸（如L-谷氨酸）、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、（+）-L-乳酸、（±）-DL-乳酸、乳糖酸、马来酸、苹果酸、（-）-L-苹果酸、丙二酸、（±）-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、（+）-L-酒石酸、硫氰酸、 p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸组成的组；所述碱为碱金属、碱土金属的氢氧化物。
有益效果
发明人通过计算研究以及疾病模型证实：
Fostamatinib、Regorafenib和褪黑素均可以显著下调Runx2的表达量，对Runx2异常高表达的癌症具有显著的靶向治疗效果，是高效的Runx2表达量调降试剂，特别是实验室用Runx2表达量调降试剂。
通过使用Fostamatinib、Regorafenib和褪黑素中的一种，或组合使用，或与其他已知的抗肿瘤药物联用，可以有效地提高疗效和/或减少副作用。
Fostamatinib、Regorafenib和褪黑素可接受的盐，在体内或细胞环境下，可以产生与Fostamatinib、Regorafenib和褪黑素相同或相近的作用，也具有相应的疗效或作用。
 附图说明
图1是Fostamatinib分别作用于肺癌细胞A549和肺癌细胞H1299 8h后的RUNX2蛋白表达水平；
图2是Fostamatinib分别作用于肺癌细胞A549和肺癌细胞H1299 8h后的RUNX2 mRNA表达水平；
图3是Fostamatinib分别作用于肺癌细胞A549和肺癌细胞H1299 6h后的RUNX2蛋白表达水平；
图4是Fostamatinib分别作用于肺癌细胞A549和肺癌细胞H1299 6h后的RUNX2 mRNA表达水平；
图5是不同浓度Fostamatinib处理肝癌细胞BEL-7402 6h后的RUNX2蛋白表达水平；
图6是fostamatinib腹腔注射对小鼠RUNX2 mRNA表达水平的影响。
 本发明的实施方式
高表达的含义为本领域公认的，即与正常组织相比，其表达量相对显著提高。一般而言，其表达量是正常组织中的1.5倍、2倍、3倍、5倍或更多。。
化合物药学上可接受的药用盐可以通过常规的化学方法从母体化合物合成，如在 Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor),ISBN:3-90639-026-8, Hardcover, 388 pages, August 2002中描述的方法。一般来说，这些盐可以由化合物的游离碱和酸在水或有机溶剂或二者的混合液中反应制得；通常，使用非水介质如***、乙酸乙酯、乙醇、异丙醇或乙腈。
酸加成盐可以通过各种酸（无机酸和有机酸）制得。酸加成盐的实例包括由酸制成的盐，所述酸选自由乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸（如L-抗坏血酸）、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、（+）樟脑酸、樟脑-磺酸、（+）-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸（如D-葡萄糖醛酸）、谷氨酸（如L-谷氨酸）、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、（+）-L-乳酸、（±）-DL-乳酸、乳糖酸、马来酸、苹果酸、（-）-L-苹果酸、丙二酸、（±）-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、（+）-L-酒石酸、硫氰酸、 p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸组成的组。
发明人通过计算研究和初步的相关疾病模型实验研究证实：
1)      Fostamatinib、Regorafenib和褪黑素均可以显著下调Runx2的表达量，对Runx2异常高表达的癌症具有显著的靶向治疗效果，是高效的Runx2表达量调降试剂，特别是实验室用Runx2表达量调降试剂。
2)      通过使用Fostamatinib、Regorafenib和褪黑素中的一种，或组合使用，或与其他已知的抗肿瘤药物联用，可以有效地提高疗效和/或减少副作用。
3)      Fostamatinib、Regorafenib和褪黑素可接受的盐，在体内或细胞环境下，可以产生与Fostamatinib、Regorafenib和褪黑素相同或相近的作用，也具有相应的疗效或作用。
初步的实验如果如下：
对肿瘤细胞对 RUNX2 蛋白和 mRNA 表达的影响
细胞接种于中号皿（6cm）中，过夜培养，待细胞汇合度为80%时，弃去原培养基，PBS润洗细胞后，换入含有终浓度为10uM或其他浓度的Fostamatinib，作用6～12小时后，收取细胞，提取RNA和蛋白液，分别通过Western blot和qPCR实验检测RUNX2的蛋白和mRNA表达变化。
实验结果如图1～5所示，其中：
图1显示Fostamatinib分别作用于肺癌细胞A549和肺癌细胞H12998h后，RUNX2蛋白表达水平有下降的趋势 (图中，F表示Fostamatinib)。
图2显示Fostamatinib分别作用于肺癌细胞A549和肺癌细胞H1299 8h后，RUNX2的mRNA水平出现较明显降低。
图3显示Fostamatinib分别作用于肺癌细胞A549和肺癌细胞H1299 6h后，RUNX2蛋白表达水平有一定程度的下降趋势 (图中，F表示Fostamatinib，更换了抗体)。
图4显示Fostamatinib分别作用于肺癌细胞A549和肺癌细胞H1299 6h后，RUNX2的mRNA水平出现较明显降低。
图5是分别采用0，2.5，5，10uM的Fostamatinib处理肝癌细胞BEL-7402 6h后，发现肝癌细胞蛋白水平出现较明显降低并且呈剂量依赖性。
上述实验结果表明Fostamatinib可以很好地抑制RUNX2的mRNA的表达，具有抗肿瘤作用。
动物实验（腹腔注射）
药物：FostamatinibMCE(HY-13038A)
小鼠：8周龄C57BL/6雄性小鼠
给药浓度：40mg/kg
给药方式：腹腔注射
实验步骤：将小鼠随机分为两组，实验组（fostamatinib）与对照组（mock），每日实验前精确称取一定量的fostamatinib，溶解于0.5%CMC(硝甲基纤维素)中，充分吹打均匀为均一的悬液，配制浓度为4mg/ml，现用现配。按照每只小鼠100ul/10g的注射量进行腹腔注射，连续注射4天，最后一次注射后48小时取小鼠肝脏组织，抽提RNA，通过实时荧光定量PCR（qPCR）方法检测RUNX2的mRNA表达水平。实验如果如图6所示。可以看出，fostamatinib可以显著降低RUNX2的mRNA表达水平，具有抗肿瘤作用。

Claims (12)

  1. 组合物在制备调降Runx2表达试剂中的应用，所述组合物的活性成分选自Fostamatinib及其可接受的盐、Regorafenib及其可接受的盐和褪黑素及其可接受的盐中的至少一种。
  2. 根据权利要求1所述的应用，其特征在于：所述盐为化合物的酸或碱加成盐；优选的，所述酸选自由乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、（+）樟脑酸、樟脑-磺酸、（+）-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸、谷氨酸、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、（+）-L-乳酸、（±）-DL-乳酸、乳糖酸、马来酸、苹果酸、（-）-L-苹果酸、丙二酸、（±）-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、（+）-L-酒石酸、硫氰酸、 p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸组成的组；所述碱为碱金属、碱土金属的氢氧化物。
  3. 根据权利要求1所述的应用，其特征在于：所述应用为实验用。
  4. 组合物在制备抗肿瘤药物中应用，其特征在于：所述组合物的活性成分包括Fostamatinib及其可接受的盐、Regorafenib及其可接受的盐和褪黑素及其可接受的盐中的至少一种。
  5. 根据权利要求4所述的应用，其特征在于：所述肿瘤为具有Runx2高表达指征的肿瘤。
  6. 根据权利要求5所述的应用，其特征在于：所述肿瘤选自乳腺癌、肺癌、肺腺癌、***癌、多发性骨髓瘤、乳腺恶性叶状肿瘤。
  7. 根据权利要求5所述的应用，其特征在于：所述组合物还包括至少一种对肿瘤具有治疗作用的已知活性成分。
  8. 根据权利要求4所述的应用，其特征在于：所述盐为化合物的酸或碱加成盐；优选的，所述酸选自由乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、（+）樟脑酸、樟脑-磺酸、（+）-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸、谷氨酸、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、（+）-L-乳酸、（±）-DL-乳酸、乳糖酸、马来酸、苹果酸、（-）-L-苹果酸、丙二酸、（±）-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、（+）-L-酒石酸、硫氰酸、 p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸组成的组；所述碱为碱金属、碱土金属的氢氧化物。
  9. 一种靶向***的方法，包括：
    对肿瘤患者的样品进行检测，确定Runx2是否高表达；
    针对Runx2高表达的患者，给予治疗量的组合物，所述组合物的活性成分包括Fostamatinib及其可接受的盐、Regorafenib及其可接受的盐和褪黑素及其可接受的盐中的至少一种。
  10. 根据权利要求9所述的方法，其特征在于：Runx2高表达定义为与正常组织相比，其表达量相对显著高。
  11. 根据权利要求9所述的方法，其特征在于：还包括给予一种对肿瘤具有治疗作用的已知活性成分。
  12. 根据权利要求9所述的方法，其特征在于：所述盐为化合物的酸或碱加成盐；优选的，所述酸选自由乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、（+）樟脑酸、樟脑-磺酸、（+）-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸、谷氨酸、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、（+）-L-乳酸、（±）-DL-乳酸、乳糖酸、马来酸、苹果酸、（-）-L-苹果酸、丙二酸、（±）-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、（+）-L-酒石酸、硫氰酸、 p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸组成的组；所述碱为碱金属、碱土金属的氢氧化物。
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