WO2022012329A1 - Utilisation d'un composé ayant un effet synergique dans le traitement des tumeurs - Google Patents

Utilisation d'un composé ayant un effet synergique dans le traitement des tumeurs Download PDF

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WO2022012329A1
WO2022012329A1 PCT/CN2021/103412 CN2021103412W WO2022012329A1 WO 2022012329 A1 WO2022012329 A1 WO 2022012329A1 CN 2021103412 W CN2021103412 W CN 2021103412W WO 2022012329 A1 WO2022012329 A1 WO 2022012329A1
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compound
tumor
drug
targeted
afatinib
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Chinese (zh)
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冯贻东
唐田
黄汉敏
冯汉林
杨经安
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深圳海王医药科技研究院有限公司
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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
    • A61K31/495—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
    • 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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further 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
    • A61K31/395—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • A61K31/395—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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • 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 a new use of a new compound (disclosed in Chinese patent application: 201610890235.1) in the field of pharmacy, in particular to the preparation of a drug for enhancing anti-tumor effect in combination with tumor-targeted small molecules or targeted immune drugs the use of.
  • Tumor drug resistance or decreased treatment effect is a difficult clinical problem. According to statistics, more than 90% of the deaths of tumor patients will be affected by tumor drug resistance.
  • the drug resistance of tumors can be divided into two categories: 1. Primary drug resistance (PDR), 2. Multidrug resistance (MDR) Research progress of medicinal properties, article number: 1674-7860 (2019) 27-0071-05).
  • PDR Primary drug resistance
  • MDR Multidrug resistance
  • the previous researches on drug resistance mostly focused on the research of chemotherapeutic drugs.
  • the mechanism of drug resistance of chemotherapeutic drugs is diverse, and there are many relevant targeted studies. With the progress of drug development, while the research on chemotherapeutic drugs continues to progress, targeted therapy has gradually become another important treatment method for tumor clinical treatment. Including small molecule targeted drugs, monoclonal antibody targeted drugs and cell biological therapy and other methods.
  • the drug resistance mechanisms of chemotherapeutic drugs include drug efflux (such as p-glycoprotein, multidrug resistance-related proteins, etc.), increased activity of drug metabolizing enzymes (such as glutathione transferase II, cyclooxygenase 2, protein kinases, etc.) C, etc.), abnormal apoptosis genes (such as Bcl-2, nuclear factor kB, HIF, etc.); abnormal cytokines, abnormal apoptosis pathways, enhanced DNA repair, etc. are also one of the factors that cause chemotherapy resistance (quoted from: Sun Xiaoran et al., Research Progress of Tumor Multidrug Resistance Mechanisms, Article No.: 1672-4992-(2017) 01-0164-03).
  • drug efflux such as p-glycoprotein, multidrug resistance-related proteins, etc.
  • drug metabolizing enzymes such as glutathione transferase II, cyclooxygenase 2, protein kinases, etc.
  • chemoresistance in addition to chemoresistance factors, the downregulation or mutation of therapeutic target proteins or genes can lead to the failure of targeted therapy.
  • drug resistance to targeted therapy the development of a new generation of targeted drugs is often used to make up for the failure of clinical treatment caused by the drug resistance of the previous generation, or to replace it with other therapeutic drugs or treatment methods, resulting in clinical patients unable to continue to use effective treatment methods.
  • osimertinib is mainly used to treat afatinib-resistant lung cancer, and the cost of treatment is significantly increased.
  • fourth-generation drugs developed and marketed for osimertinib-resistant.
  • trastuzumab is blocked due to the target mutation, which leads to drug resistance. It should be replaced with other second-line treatment drugs with stronger adverse effects, or treatment drugs with higher treatment costs (quoted from: Li Wei et al., HER2 positive The drug resistance mechanism of breast cancer drug trastuzumab and research progress of new generation targeted drugs, Chinese Journal of Clinical Pharmacology, 2014, (1). Or use it in combination with monoclonal antibodies such as Pertuzumab to increase the therapeutic effect. At present, in order to relatively reduce the adverse reactions caused by drugs and increase the therapeutic effect, patients who meet the conditions of targeted therapy often use multiple targeted drugs in combination to treat tumors, but the problem of drug resistance cannot be effectively avoided.
  • a synergist for targeted therapy can greatly reduce the probability of switching to a drug with a higher treatment price, which will greatly reduce the cost of medication for patients in clinical practice, and can minimize the cost of switching to other second-line drugs.
  • Adverse reactions It can effectively delay the emergence of drug resistance and avoid the dilemma that the final patient has no drug available due to drug resistance to the greatest extent.
  • PI3K/AKT signaling pathway inhibitors have once become the most promising drugs for reversing tumor MDR. More reactions, its clinical application value is low.
  • One object of the present invention is to provide the use of a compound represented by formula (I) in combination with a tumor-targeted small molecule or a targeted immune drug to enhance the anti-tumor effect.
  • Another object of the present invention is to provide an application of a compound represented by formula (I) in the preparation of a drug that can be used in combination with a tumor-targeting small molecule or a targeted immune drug to enhance the anti-tumor effect.
  • the compound represented by formula (I) has the effect of inhibiting the activity of PI3K in tumor cells, thereby improving the anti-tumor effect of tumor-targeted small molecules or targeted immune drugs, and can reduce the dosage of targeted drugs in clinical practice.
  • the frequency of medication can not only increase the therapeutic effect of tumor-targeted therapy in clinical practice, but also further reduce related adverse reactions and toxicity, so that patients can obtain better therapeutic effect and quality of life.
  • the dosage of the compound When combined with tumor-targeted small molecules or targeted immune drugs, the dosage of the compound is 1 mg-75 mg/kg body weight/time according to the therapeutically effective amount in the in vivo experiments of animals (mice).
  • the dosage converted to the human body is 5mg-375mg/60kg body weight/time, and the more preferred human dosage range is 5mg -300mg/60kg body weight/time.
  • Another object of the present invention is to provide a kind of compound in the present invention as a medicinal ingredient, add pharmaceutically acceptable pharmaceutical excipients, or add other medically necessary auxiliary active ingredients (traditional Chinese medicine, herbal medicine, chemical medicine) , biological drugs, etc.), and the purposes of the pharmaceutical composition prepared by conventional methods in the art, that is, the pharmaceutical composition is used in combination with targeted small molecules or targeted antibody drugs in tumor targeted therapy to enhance the anti-tumor effect. the use of.
  • the dosage form of the pharmaceutical preparation is a preparation for injection administration or oral administration or inhalation administration (including but not limited to: injection water for injection, lyophilized powder for injection, emulsion for injection , injection suspensions, liposome injections, microsphere injections, nanoparticle injections, reservoir-type controlled-release injections, gel-type injections, etc.; in terms of injection devices and packaging, including single-dose/multi-dose needle-free injections, Powder syringes, prefilled injections, powder/liquid premixed syringes, hypodermic injection syringes, etc.; including but not limited to tablets, oral liquids, powders, granules, pills, sustained-release oral dosage forms, etc.; inhalation preparations include but not limited to not limited to sprays, powder aerosols, aerosolized therapeutic dosage forms, dry powder for inhalation, etc.).
  • injection water for injection lyophilized powder for injection
  • emulsion for injection injection suspensions
  • liposome injections micro
  • the pharmaceutical excipients used in the preparation of the pharmaceutical composition in the present invention include aqueous solvents, non-aqueous solvents, additives for preparations, additives for increasing the solubility of the main drug, additives for helping the main drug to suspend or emulsify, preventing Additives for the oxidation of main drugs, additives for adjusting pH value, additives for inhibiting the reproduction of microorganisms, additives for alleviating pain, etc.
  • the content of the active ingredient compound in the composition is 10 mg-750 mg, and the preferred content is 20 mg-500 mg.
  • the content refers to the total amount of the active ingredient compound in a single-use medicine, and those skilled in the art can determine the unit dosage form (including but not limited to each bottle, each tablet, each capsule, each bottle) according to the content according to the needs of the preparation and use. , per milliliter, per ten milliliters, per lift, etc.) of the active ingredient compound.
  • the invention has the advantages of simple prescription, high safety, convenient use, strong clinical implementation feasibility, and strong social significance and economic benefit.
  • the present invention mainly investigates the synergistic effect of five compounds represented by formula (I) on trastuzumab-resistant tumor cells through Example 1.
  • the results showed that when trastuzumab was used in combination with each of the compounds C7, C10, C12, C15, and C17, the viability of tumor cells was significantly reduced, indicating that each compound had a synergistic effect on trastuzumab resistance. effect.
  • Each compound can effectively reduce the proportion of phosphorylated Akt in tumor cells, which reflects the inhibitory ability of each compound on PI3K pathway activity.
  • Example 2 of the present invention the therapeutic effect of each representative compound in combination with trastuzumab on tumor transplanted in immunodeficient mice was investigated. After each representative compound was used in combination with trastuzumab, the proliferation of tumors was significantly inhibited, and the tumor volume showed a significant decreasing trend. Different numbers of animals appeared in each combination group. The tumor volume was too small to be seen by the naked eye. As can be seen, volume measurement is not possible.
  • the strength of each representative compound to increase the antitumor effect of trastuzumab was C7>C10>C12>C17>C15.
  • Example 3 of the present invention the therapeutic effect of each representative compound in combination with Cetuximab (cetuximab) on transplanted tumors in immunodeficient mice was investigated.
  • the results showed that at a dose of 1 mg/kg, Cetuximab could exert a mild anti-tumor effect, and the anti-tumor effect of other representative compounds alone was not strong; when each compound was used in combination with Cetuximab, the anti-tumor effect was significantly enhanced.
  • Example 4 the sensitization effects of compounds C7, C10, C12, C15, and C17 on afatinib-resistant cells were investigated respectively.
  • the experimental results showed that after each compound was used in combination with afatinib, the proliferation of tumor cells was significantly inhibited, suggesting that each compound could effectively inhibit the drug-resistant activity of drug-resistant cell lines and increase the sensitivity to afatinib.
  • the compound can effectively reduce PI3K activity in tumor cells.
  • Example 5 the therapeutic effects of compounds C7, C10, C12, C15, C17 and targeted small molecule drug afatinib on the non-small cell lung cancer H1975 nude mouse transplantation model were respectively investigated.
  • the experimental results showed that after afatinib was used in combination with each compound at a dose of 10 mg/kg, the tumors in each combination group were significantly inhibited, but at the same time, the body weight of the animals was not significantly affected. It is suggested that each compound can effectively improve the anti-tumor effect of afatinib without affecting the safety of animals.
  • Example 6 is used to investigate the protective effect of compounds C7, C10, C12, C15, and C17 on reducing the toxicity of afatinib. Combining different compounds (5 mg/kg) on the basis of the same dose of afatinib, each compound can effectively reduce the mortality of animals caused by afatinib.
  • Example 7 the therapeutic effect of each compound in combination with afatinib on the transplantation model of human epidermal cancer cells A431 in nude mice was investigated.
  • afatinib can significantly improve the anti-tumor effect after combining with each compound.
  • Example 8 the sensitizing effect of each compound on osimertinib AZD9291-resistant cells was investigated respectively.
  • the experimental results showed that after each compound was used in combination with osimertinib, the proliferation of tumor cells was significantly inhibited, suggesting that each compound could effectively inhibit the drug-resistant activity of drug-resistant cell lines, and increased the dose of osimertinib without increasing the dose. Sensitivity of resistant cells to osimertinib.
  • Example 9 the therapeutic effect of each compound in combination with Sorafenib (Sorafenib) on tumor transplanted in immunodeficient mice was investigated.
  • the results show that at a dose of 10 mg/kg, Sorafenib can exert a mild anti-tumor effect, and the anti-tumor effect of other compounds alone is not strong; when each compound is used in combination with Sorafenib, the anti-tumor effect is significantly enhanced.
  • Example 11 the therapeutic effect of compound 7 in combination with Sorafenib of different doses on the transplanted tumor of immunodeficient mice was investigated.
  • the results showed that at a dose of 10 mg/kg, Sorafenib could exert a mild anti-tumor effect, and when compound C7 was used in combination with Sorafenib, the anti-tumor effect was significantly enhanced.
  • the antitumor effect of sorafenib increased, showing an obvious dose-dependent.
  • Figure 3 The therapeutic effects of compounds C7, C10, C12, C15, C17 in combination with cetuximab on tumor transplanted in immunodeficient mice, respectively.
  • Figure 4 Sensitization of afatinib-resistant cells by compounds C7, C10, C12, C15, and C17.
  • Figure 7 Effects of compounds C7, C10, C12, C15, and C17 on alleviating the weight loss of tumor-bearing mice caused by afatinib.
  • Figure 11 The therapeutic effects of compounds C7, C10, C12, C15, C17 in combination with sorafenib on tumor transplanted in immunodeficient mice, respectively.
  • mice male SCID male mice, female nu/nu mice, female CD-1nude mice, weighing 18-22 grams, were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.
  • Drug preparation method monoclonal antibodies can be diluted with normal saline to the corresponding concentration; chemical drugs are injected with normal saline or DMSO to be diluted to the corresponding concentration; chemical drugs are prepared by oral route of drug preparation with an appropriate amount of DMSO dilution, using 5 % CMC-Na solution was thoroughly mixed and administered.
  • trastuzumab-resistant cells (1) Establishment of trastuzumab-resistant cells: according to the literature (A Crawford et al, "Targeting Bcl-2 in Herceptin-Resistant Breast Cancer Cell Lines", Current Pharmacogenomics and Personalized Medicine, Volume 9, Issue 3, 2011) The method establishes the culture of trastuzumab-resistant BT-474 cells by incubating in the environment of trastuzumab at a low concentration for a long time.
  • the specific groups are as follows: blank group (no drug added, normal culture), each compound group (C7 group, C10 group, C12 group, C15 group, C17 group; the concentration is 50nM), trastuzumab (40 ⁇ g/mL) Group, each compound (concentration of 50 nM) and trastuzumab (40 ⁇ g/mL) combined group, a total of 12 groups.
  • the cells were cultured for 72 hours, and the number of viable cells was measured by MTT method. Three wells were used for each same intervention method, and two 96-well plates were inoculated repeatedly, and the experiment was repeated twice. The cell viability of all groups was compared with the blank group, and the survival ratio of tumor cells was calculated.
  • trastuzumab-resistant tumor cells In vitro cell tests showed that each compound alone had a certain inhibitory activity on trastuzumab-resistant tumor cells, but did not show significant inhibitory effect; while trastuzumab inhibited drug-resistant cells at a concentration of 40 ⁇ g/mL Poor ability.
  • trastuzumab When trastuzumab was used in combination with each compound, the viability of tumor cells was significantly reduced, showing the synergistic effect of each compound against trastuzumab resistance (shown in Figure 1).
  • each compound could effectively reduce the proportion of phosphorylated Akt in tumor cells, which further reflected the inhibitory ability of each compound on PI3K pathway activity.
  • each compound may reduce the resistance of trastuzumab through the PI3K pathway and increase its tumor suppressive effect.
  • OBJECTIVE To investigate the therapeutic effect of each compound in combination with trastuzumab on transplanted tumors in immunodeficient mice.
  • Animal grouping and administration methods are as follows: 15 animals in each group were divided into blank group, trastuzumab group (administered 30 mg/kg for the first time, followed by 15 mg/kg dose), and each compound alone administration group (Compounds C7, C10, C12, C15, C17; each dose is 5 mg/kg), each compound is combined with trastuzumab and the use group (trastuzumab group is administered 30 mg/kg for the first time, followed by 15 mg/kg kg dose; compound was dosed at 5 mg/kg).
  • T the tumor volume of the administration group after the last administration
  • T0 the tumor volume of the administration group before the first administration
  • C the tumor volume of the blank group after the last administration of the experiment
  • C0 the experiment The tumor volume of the blank group before the first administration
  • OBJECTIVE To investigate the therapeutic effect of each representative compound in combination with cetuximab on tumor transplanted in immunodeficient mice.
  • the animal groups were set as blank control group (Vehicle group), targeted antibody drug cetuximab (Cetuximab 1mg/kg) group, each compound used alone group (compound group) C7, compound C10, compound C12, compound C15, compound C17), the combination group of each compound and the targeting antibody drug (compound+Cetuximab (1 mg/kg)).
  • each combination group except Cetuximab, each compound was administered at a dose of 5 mg/kg), each combination compound was administered approximately 0.5-4 hours after administration of Cetuximab for 10 consecutive weeks, and tumors were measured after the final administration. size.
  • the induction started with 0.5nM afatinib, and after the cells recovered to 90% confluence and 1:3 passage, fixed for 3 days after passage once, the maintenance concentration of afatinib was increased, and the maintenance concentration of afatinib was gradually increased. Increase to 2nM, 6nM, 10nM, 16nM, after the 16nM concentration was maintained for one month, the maintenance concentration was no longer increased for the experiment.
  • the drug-resistant tumor cells were intervened with different incubation conditions.
  • the results showed that the drug-resistant cell lines with afatinib could proliferate stably, and the tumor cell lines with each representative compound alone proliferated stably, but they were all slower than those without the addition of afatinib.
  • the proliferation rate of cell lines of any drug after each compound was used in combination with afatinib, the proliferation of tumor cells was significantly inhibited, suggesting that each compound can effectively inhibit the drug-resistant activity of drug-resistant cell lines and increase its resistance to afatinib Ni's sensitivity (see Figure 4).
  • OBJECTIVE To study the therapeutic effect of each compound in combination with afatinib on the transplanted model of non-small cell lung cancer H1975 in nude mice.
  • the H1975 cells were cultured to a sufficient logarithmic phase, and the collected cell suspension was inoculated into the right armpit of nude mice, and the inoculation amount should reach the order of 106 cells/point.
  • the tumor growth was continuously observed, and the tumor-bearing nude mice with well-growing tumors were sacrificed by de-neck. After routine disinfection, the tumor was peeled off, and the translucent flesh-colored part was selected and cut into small pieces of about 2 mm ⁇ 2 mm ⁇ 2 mm, and inoculated subcutaneously in the right armpit. When it is about 300mm 3 , it is used for the formal test after at least one passage in vivo.
  • the tumor grew to be about 100mm 3, depending on the volume of tumor block were randomly divided into control group, the animals, afatinib (10mg / kg, 30mg / kg ) group, afatinib (10mg / kg) in combination with each compound group (5 mg/kg).
  • Oral administration (the control group was given the same volume of deionized water), once a day, for 14 consecutive days. During the administration period, the long diameter, short diameter and body weight of the tumor were measured, twice a week. 24h after the last administration, the body weight and tumor diameter were measured, and the animals were sacrificed to dissect the tumor tissue and weighed.
  • the H1975 tumor cell line is a T790M-mutated afatinib-resistant tumor cell line
  • afatinib can produce better anti-tumor effects at high doses, so at low doses
  • the inhibitory effect of afatinib on H1975 was not obvious at the dose.
  • the dose of afatinib was 10 mg/kg, the animals did not experience significant body weight loss, but the antitumor effect of afatinib was significantly reduced.
  • afatinib In order to produce the expected therapeutic effect, increasing the dose of afatinib to 30mg/kg can effectively inhibit the proliferation of H1975 non-small cell lung cancer tumor, but it has a significant effect on the body weight of animals, significantly reducing the body weight of animals, suggesting that at 30mg/kg Although afatinib has a good tumor inhibitory effect at the dose, it also has relatively large systemic toxicity.
  • each representative compound can effectively improve the antitumor effect of afatinib without affecting the safety of animals.
  • each representative compound can effectively reduce the mortality of animals caused by afatinib (see Figure 8).
  • the tumor inhibitory activity could be significantly reduced, and the dose of afatinib was 3 mg/kg, and the effective dose was significantly reduced. And there was no significant effect on the body weight of the animals in the combination group.
  • Sorafenib can exert a mild anti-tumor effect, and the anti-tumor effect of other representative compounds alone is not strong; when each compound is used in combination with Sorafenib, the anti-tumor effect significantly enhanced.

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Abstract

L'invention concerne l'utilisation d'un composé représenté par la formule (I) utilisé en association avec une petite molécule ciblant une tumeur ou un médicament immunitaire ciblé pour améliorer un effet antitumoral, et l'utilisation pharmaceutique de celui-ci. Le médicament contenant le composé peut être administré par injection ou par administration orale, de telle sorte que l'effet antitumoral d'un médicament à petite molécule ciblé et d'un médicament anticorps immunitaire peut être amélioré.
PCT/CN2021/103412 2020-07-14 2021-06-30 Utilisation d'un composé ayant un effet synergique dans le traitement des tumeurs WO2022012329A1 (fr)

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CN115137831A (zh) * 2022-06-22 2022-10-04 中国海洋大学 虾青素在制备抗血管生成药物增效剂中的应用以及一种药物组合物

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CN111840291B (zh) * 2020-07-14 2021-12-21 深圳海王医药科技研究院有限公司 一种在肿瘤治疗中具有增效作用的化合物的应用
CN115120731A (zh) * 2022-07-12 2022-09-30 四川大学华西医院 一种靶向蛋白酶体治疗乳腺癌的药物应用

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