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WO2022116369A1 - Préparation et composition d'un nouveau type de complexe d'agoniste de sting et utilisation de ce dernier dans un médicament antitumoral - Google Patents

Préparation et composition d'un nouveau type de complexe d'agoniste de sting et utilisation de ce dernier dans un médicament antitumoral Download PDF

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WO2022116369A1
WO2022116369A1 PCT/CN2021/072068 CN2021072068W WO2022116369A1 WO 2022116369 A1 WO2022116369 A1 WO 2022116369A1 CN 2021072068 W CN2021072068 W CN 2021072068W WO 2022116369 A1 WO2022116369 A1 WO 2022116369A1
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complex
folic acid
sting agonist
cancer
platinum
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谭瀛轩
向道凤
谭相石
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Hangzhou Xingao Biotechnology Co Ltd
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Hangzhou Xingao Biotechnology Co Ltd
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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the invention belongs to the technical field of biomedicine, and in particular relates to the preparation and composition of a new type of STING agonist complex and its application in the preparation of antitumor drugs.
  • Tumor is one of the major diseases that seriously endanger human life and health. According to WHO statistics, the number of cancer cases worldwide may increase to 24 million each year. At present, the methods used to treat tumors are mainly surgery, radiotherapy and chemotherapy. Chemotherapy is the main method currently used to treat malignant tumors. The biggest advantage of chemotherapy drugs is that they can quickly inhibit tumor proliferation and metastasis, and control the disease in a short period of time. Cisplatin-based antitumor drugs have become one of the most effective drugs for the clinical treatment of malignant tumors due to their unique mechanism of action and broad anticancer spectrum. However, its toxic and side effects, drug resistance or cross-resistance, and unclear targeting have become obstacles that limit its expansion of clinical applications.
  • chemotherapeutic drugs on normal cells, tissues and organs of the human body are the biggest obstacles and disadvantages that limit the further use of chemotherapeutic drugs.
  • chemotherapy does not reverse the tumor tissue in the body, and when chemotherapy is stopped for a period of time, the tumor may recur and worsen. Therefore, how to seek more efficient and less toxic cisplatin metal complexes in the process of clinical treatment has become an urgent problem to be solved. Therefore, based on single-functional cisplatin metal complexes, which have targeting and complex functions, and can enhance efficacy and reduce toxicity, the research on this type of innovative anticancer platinum metal complexes has become an international hotspot.
  • Tumor immunotherapy refers to the most rapidly developed method of tumor treatment in the academic and medical circles in recent years. Tumor immunotherapy refers to the therapy that kills tumor cells and tissues by activating the human immune system and immune cells and relying on their own immune function. Different from traditional surgery, chemotherapy and radiotherapy, the direct target of tumor immunotherapy is not tumor tissue, but the body's own immune system. The human immune system is complex and sophisticated. Numerous immune cells perform their respective functions and protect the body's health through different mechanisms. Immunotherapy utilizes the body's own immune function to attack tumor cells without the side effects of traditional chemotherapy and radiotherapy, nor drug resistance, and controls the development and metastasis of tumors.
  • Tumor immunotherapy has been proved to be an anti-tumor therapy with significant clinical therapeutic effect and great advantages.
  • immunotherapy has been successfully applied to the treatment of various tumors such as melanoma, lymphoma, breast cancer, lung cancer and leukemia in clinical work. treat.
  • Folic acid is an important B-group water-soluble vitamin, also known as vitamin M. It was isolated from spinach in 1941, also known as pteroylglutamic acid. As the importance of folic acid in the diet is gradually recognized, especially the research on folic acid and birth defects, cardiovascular diseases and tumors is gradually deepening, folic acid has become an extremely important micronutrient. Folic acid plays an important role in the synthesis of purine and pyrimidine, the interaction of amino acids and some methylation reactions. Folic acid is also often used as a targeting agent for targeting folate receptors on the surface of cancer cells, and is used in the preparation of various anticancer drug targeting preparation materials.
  • ER endoplasmic reticulum
  • STING endoplasmic reticulum
  • cGAMP cyclic cGMP-AMP dinucleotide synthase
  • cGAMP is a cytoplasmic DNA sensor, which acts as a second messenger to stimulate the induction of INF- ⁇ through STING, mediates the activation of TBK1 and IRF-3, and then initiates the transcription of INF- ⁇ gene.
  • cGAMP As a secondary messenger molecule, cGAMP induces the production of interferon IFN- ⁇ and other cytokines through the STING protein pathway on the endoplasmic reticulum membrane, regulates the expression of downstream proteins, induces cell growth arrest and apoptosis, and produces antiviral effects.
  • the STING pathway can regulate the innate immune recognition of immunogenic tumors and promote the antitumor effect of interferons.
  • cGAMP is a key stimulator of the innate immune response mediated by cGAS-cGAMP-STING-IRF3 and is an endogenous agonist/activator of STING, therefore, cGAMP has a role in promoting antitumor immune response.
  • the invention researches and prepares a new type of natural immune STING agonist and a stable complex composed of folic acid and/or folic acid platinum metal complex.
  • This new type of complex combines active immune STING agonist and folic acid or folate platinum metal complex into one, which has targeting and complex functions, and can synergize and reduce toxicity.
  • immune STING agonist/or folate platinum metal complex alone, this new type of STING agonist complex has significantly improved anti-tumor efficacy, and can significantly reduce the toxic and side effects of cisplatin metal complex, which is an ideal
  • the innovative compound anti-tumor drug has potential anti-tumor clinical application prospects.
  • the present invention reports a new type of STING agonist complex, which is a stable complex formed by STING agonist and folic acid or folate platinum metal complex through hydrogen bonding and intermolecular force.
  • This new type of STING agonist complex can effectively inhibit the growth and tumor metastasis of solid tumors, and its anti-tumor efficacy is significantly better than that of single use of STING agonist or folate platinum metal complex.
  • the anti-tumor efficacy of the STING agonist and folate platinum metal complex complex is significantly better than that of folate platinum metal complex, and also significantly better than oxaliplatin, in particular, it can significantly reduce the toxic and side effects of cisplatin metal complex anti-tumor drugs .
  • the specific invention contents include:
  • composition of the novel STING agonist complex is composed of an innate immune pathway STING agonist and folic acid or a cisplatin complex containing a folic acid ligand.
  • the specific features are: (1) Innate immune pathway STING agonists refer to innate immune pathway (cGAS-STING-cGAMP-IRF3 pathway) STING agonists, including but not limited to cyclic dinucleotides (such as 2'3'-cGAMP ) and its various derivatives.
  • Folic acid is a water-soluble B vitamin, the molecular formula is C19H19N7O6, also known as pteroylglutamic acid;
  • Folic acid platinum complex is a cisplatin metal complex containing folic acid ligands, including but not limited to cyclohexane Folic acid cisplatin metal complexes such as diamine folic acid platinum (II) and diamine folic acid platinum (II);
  • the composition of the new immune agonist complex is characterized by: STING agonist and folic acid or folic acid-containing platinum metal The complexes are tightly combined into stable integrated complexes through hydrogen bonds and intermolecular interactions;
  • a STING agonist such as 2'3'-cGAMP
  • novel STING agonist complex in the preparation of antitumor drugs.
  • This type of compound drug is used in the treatment of various tumors, including but not limited to colorectal cancer, breast cancer, ovarian cancer, prostate cancer, pancreatic cancer, testicular cancer, lung cancer, nasopharyngeal cancer, esophageal cancer, kidney cancer, glioma , melanoma, malignant lymphoma, head and neck cancer, thyroid cancer and osteosarcoma and other solid tumors.
  • Tumor metastases include but are not limited to lung metastases, liver metastases, lymphatic metastases, brain metastases, and the like.
  • This new type of STING agonist compound drug includes unit preparations of different specifications and pharmaceutically acceptable pharmaceutical preparations, including but not limited to intravenous injection, intramuscular injection, subcutaneous injection, intravenous drip, nasal drip, oral administration, etc.
  • pharmaceutically acceptable pharmaceutical preparations including but not limited to intravenous injection, intramuscular injection, subcutaneous injection, intravenous drip, nasal drip, oral administration, etc.
  • Cyclic dinucleotide 2'3'-cGAMP is synthesized by cyclic dinucleotide synthase (cGAS) under the activation conditions after binding to DNA according to the literature method, and the purity is above 98% (Li P.W, et al. , Immunity, 2013, 39(6), 1019-1031).
  • cyclohexanediamine folic acid platinum (II) metal complex All chemical reagents were of analytical grade and were purchased from Sigma Company.
  • the specific synthesis steps of cyclohexanediamine folic acid platinum (II) metal complex are as follows: after potassium tetrachloroplatinate (1mmol) and potassium iodide (8mmol) are stirred and dissolved in 20 milliliters of purified water, cyclohexanediamine (DACH is added dropwise, 2mmol), continue to stir and react for 1 hour to produce a yellow precipitate, filter, wash with water to obtain a yellow powder, dry, mix the yellow powder with silver nitrate and dissolve it in 50 ml of water, stir and react overnight, filter to remove the gray-green precipitate AgI, The sodium hydroxide aqueous solution (2mmol) of folic acid was added dropwise to the filtrate, heated and refluxed for 2 days, filtered, and the filtrate was concentrated, placed in a refrigerator at 4 degrees
  • Platinum(II) metal complex in 70% yield The cyclohexanediamine folic acid platinum (II) metal complex was verified to be [Pt(cyclohexanediamine)(folic acid) 2 ] by mass spectrometry, elemental analysis, and platinum metal content analysis.
  • the highest nucleocytoplasmic ratio peak in the positive spectrum of mass spectrometry was 1190, which corresponds to the molecular weight of the target product of 1189.
  • the results of elemental analysis and platinum metal content analysis are as follows: measured value % (theoretical value %).
  • novel STING agonist complexes prepared in the examples are as follows:
  • Example 2 Anti-tumor effects of novel STING agonist complexes were detected using a tumor-bearing mouse model
  • BALB/C common mice C57BL/6 common mice, male, weight 20-22 g, 7-8 weeks old, SPF grade, purchased from Ncapturing Model Biotechnology Co., Ltd.
  • mice All mice foraged and drank freely and were housed at room temperature (23 ⁇ 2)°C.
  • the feed and water were all sterilized by autoclaving, and the whole experimental feeding process was SPF grade.
  • mice were injected into the tail vein, and the STING agonist complex was set to one dose group: 10 mg/kg
  • Dosing volume 100 microliters / only
  • Dosing frequency once a day for 21 consecutive days
  • the mouse colorectal cancer cell line CT26, the mouse breast cancer cell line 4T1, and the mouse lung cancer cell line LL/2 were purchased from the Cell Bank of the Chinese Academy of Sciences.
  • the cells were cultured and passaged, and the cells were collected in the logarithmic phase of the cells to make a cell suspension with a concentration of (1.0 ⁇ 10 7 ) per milliliter.
  • Each animal was successfully tumorigenic in about 8 days, and were randomly divided into 6 groups.
  • the 6 groups are A: negative control group (normal saline group), B: positive control cGAMP group (10 mg/kg), C: folic acid control group (10 mg/kg), D: cyclohexanediamine folic acid platinum (II) Metal complex (10 mg/kg), E: complex I (STING agonist folate complex) (10 mg/kg), F: complex II (STING agonist folate platinum complex complex) (10 mg/kg) . It was administered once a day for 21 consecutive days. After 21 days, the mice were sacrificed and the tumor weight was weighed.
  • the tumor inhibition rate [1-average tumor weight of experimental group (groups B, C, D, E, and F are experimental groups)/average tumor weight of group A]] ⁇ 100%
  • the mouse colorectal cancer cell line CT26 was prepared and transplanted into BalB/C ordinary mice, the mouse breast cancer cell line 4T1 was transplanted into BalB/C ordinary mice, and the mouse lung cancer Lewis tumor line LL/2 was transplanted into C57BL /6 mice to observe the anti-tumor effects of different drugs.
  • the new STING agonist complex can significantly inhibit tumor growth, and the tumor weight after 21 days of administration was significantly lower than that of the negative control group.
  • the new STING agonist complex The antitumor effects were better than those of the STING agonist cGAMP alone or the cyclohexanediamine folate platinum(II) metal complex alone, indicating that the new STING agonist complex drug has a significantly improved antitumor effect. The specific results are shown in the table below.
  • Example 3 The effect of novel STING agonist complex against tumor metastasis of mouse breast cancer 4T1-Luc
  • mice Male, weighing 20-22 g, 7-8 weeks old, SPF grade, were purchased from Ncapturing Model Biotechnology Co., Ltd.
  • mice All mice foraged and drank freely and were housed at room temperature (23 ⁇ 2)°C.
  • the feed and water were all sterilized by autoclaving, and the whole experimental feeding process was SPF grade.
  • mice were injected into the tail vein, and the STING agonist complex was set to one dose group: 10 mg/kg
  • Dosing volume 100 microliters / only
  • Dosing frequency once a day for 30 consecutive days
  • the mouse breast cancer cell line 4T1-luc (luciferase-labeled tumor cells) was donated by Zhejiang University School of Medicine. The growth and metastasis characteristics of 4T1-luc mouse breast cancer cells in BALB/C mice are very similar to those of human breast cancer.
  • This tumor is an animal model of human stage VI breast cancer. 4T1-luc spontaneously produces highly metastatic tumors that can metastasize to the lung, liver, lymph nodes, and brain, while forming a primary foci at the injection site.
  • Luciferase is a general term for a class of enzymes that catalyze the oxidation and luminescence of luciferin or firefly aldehyde in living organisms, and it comes from organisms that can emit light in nature.
  • the cells were cultured and passaged, and the cells were collected in the logarithmic phase of the cells to make a cell suspension with a concentration of (1.0 ⁇ 10 6 ) per milliliter.
  • One/only) the drug was administered on the second day after inoculation of breast cancer cells, once a day, and the patients were randomly divided into 6 groups.
  • the 6 groups were A: negative control group (normal saline group), B: positive control cGAMP group (10 mg/kg), C: folic acid group (10 mg/kg), D: cyclohexanediamine folic acid platinum (II) metal Complex (10 mg/kg), E: complex I (STING agonist folate complex) (10 mg/kg), F: complex II (STING agonist folate platinum complex complex) (10 mg/kg).
  • the tumor metastasis of breast cancer in mice was detected by a small animal in vivo optical imaging system (Perkin Elmer, IVIS Lumina XRMS Series III) (completed at Shanghai Medical College of Fudan University), on the 5th, 10th, and 30th days after administration, respectively. detection. Observing the effect of different drugs against breast cancer tumor metastasis is summarized as follows:
  • mice Male, weighing 20-22 g, 7-8 weeks old, SPF grade, were purchased from Ncapturing Model Biotechnology Co., Ltd.
  • mice All mice foraged and drank freely and were housed at room temperature (23 ⁇ 2)°C.
  • the feed and water were all sterilized by autoclaving, and the whole experimental feeding process was SPF grade.
  • mice were injected into the tail vein, and the STING agonist complex was set to one dose group: 10 mg/kg
  • Dosing volume 100 microliters / only
  • Dosing frequency once a day for 21 consecutive days
  • mice were randomly divided into 5 groups.
  • the 5 groups are A: normal group; B, negative control group (normal saline group), C: positive control oxaliplatin group (5mg/kg), D: cyclohexanediamine folic acid platinum (II) metal complex (10 mg/kg), E: complex II (complex of the STING agonist folate platinum complex) (10 mg/kg). It was administered once a day for 21 consecutive days.
  • mice were dosed for 21 days, and the percentage of body weight loss and survival rate of mice are summarized in Table 5.
  • mice weight loss(%) Survival rate (%) A, normal mouse ——— —— B, saline control —— —— C, oxaliplatin 40 (14 days) 0 (all deaths in 14 days) D, cyclohexanediamine folic acid platinum complex 20 80 E, complex II 6 100
  • platinum-containing drugs such as Oxaliplatin
  • Oxaliplatin can produce toxic side effects of blood system damage in patients, showing symptoms such as anemia, thrombocytopenia, and neutropenia. Therefore, in the experiment, we collected the peripheral blood of mice administered with the new compound and the positive control group (oxaliplatin and cyclohexyldiamine folic acid platinum complex group) for routine blood test and compared with the mice.
  • the normal control group was used to evaluate the effect of the drug on the blood system of mice.
  • the symptoms of anemia in the body are reflected in two aspects: first, the number of red blood cells (Red blood cells, RBC) decreases; second, the content of hemoglobin (Hemoglobin) decreases.
  • RBC red blood cells
  • Hemoglobin the content of hemoglobin
  • ALT alanine aminotransferase
  • Creatinine creatinine
  • Oxaliplatin caused damage to the liver and kidney of mice.
  • the ALT and Creatinine indexes of the cyclohexyldiamine folic acid-platinum complex group were much better than those of oxaliplatin, but there were still some toxic effects.
  • the new complex has minimal liver and kidney side effects in mice, and the immune agonist complex significantly reduces the toxic side effects of cisplatin.
  • ICR mice purchased from Ncapturing Model Biotechnology Co., Ltd.
  • half male and half male weighing 18-22 g, were fed with pelleted feed and had free access to food and water.
  • mice were injected with 2 g/kg of STING agonist complex (I, II) into the tail vein according to body weight, and the toxicity and death of mice were observed within 14 days after administration. It was found that the mice moved normally after a single tail vein injection. Within 14 days after administration, the mice did not die. On the 15th day, all mice were sacrificed, dissected, and each organ was examined with the naked eye, and no obvious lesions were found.
  • STING agonist complex I, II

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Abstract

Est divulgué, un complexe agoniste de STING, qui est un complexe stable formé par un agoniste de STING et de l'acide folique ou un complexe métallique de platine et d'acide folique, ayant pour effet d'inhiber la croissance tumorale et les métastases tumorales, et pouvant être utilisé pour préparer un médicament antitumoral.
PCT/CN2021/072068 2020-12-02 2021-01-15 Préparation et composition d'un nouveau type de complexe d'agoniste de sting et utilisation de ce dernier dans un médicament antitumoral Ceased WO2022116369A1 (fr)

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CN202011402681.6A CN114569627A (zh) 2020-12-02 2020-12-02 新型sting激动剂复合物的制备、组成及其在抗肿瘤药物中的应用
CN202011402681.6 2020-12-02

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CN115969982A (zh) * 2023-02-04 2023-04-18 哈尔滨医科大学 Sting激动剂在制备用于抑制肿瘤血行转移的药物中的用途

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CN117050115A (zh) * 2023-08-16 2023-11-14 南通大学 Sting激动剂msa-2的铂盐合成和肿瘤治疗应用

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CN115558022A (zh) * 2022-09-26 2023-01-03 重庆大学 一种锰掺杂蛋白免疫激动剂组装体、构建方法及其应用
CN115969982A (zh) * 2023-02-04 2023-04-18 哈尔滨医科大学 Sting激动剂在制备用于抑制肿瘤血行转移的药物中的用途

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