WO2022253222A1 - 医药组合物治疗肺癌的用途 - Google Patents

医药组合物治疗肺癌的用途 Download PDF

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WO2022253222A1
WO2022253222A1 PCT/CN2022/096233 CN2022096233W WO2022253222A1 WO 2022253222 A1 WO2022253222 A1 WO 2022253222A1 CN 2022096233 W CN2022096233 W CN 2022096233W WO 2022253222 A1 WO2022253222 A1 WO 2022253222A1
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pharmaceutical composition
inhibitor
concentration
nuclear protein
lung cancer
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French (fr)
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蔡长海
洪明奇
李培志
萧宇君
曾子育
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洪明奇
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Priority to US18/566,830 priority Critical patent/US20240261279A1/en
Priority to EP22815267.4A priority patent/EP4349340A1/en
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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further 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
    • A61K31/33—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines 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
    • A61K31/33—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
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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 invention relates to an application of a pharmaceutical composition, in particular to an application of a pharmaceutical composition containing a nucleoprotein kinase C- ⁇ inhibitor for treating lung cancer.
  • Lung cancer has always been the cancer with the highest incidence and mortality rate.
  • the cancer population in the world about 20% are lung cancer patients, and the five-year survival rate of patients is only about 15%.
  • lung cancer can be roughly divided into non-small cell carcinoma and small cell carcinoma, of which about 85% to 90% of lung cancer is non-small cell carcinoma, and different treatments can be adopted according to the degree of invasion of non-small cell carcinoma Methods: For early stage (stage I and stage II) non-small cell carcinoma, surgery can be used to completely remove the tumor. Chemotherapy is combined with radiation therapy to obtain better therapeutic effect.
  • Typical clinical target therapy drugs are epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), which can bind to epidermal growth factor receptor (EGFR) and block Interrupt information transmission, thereby achieving the effect of inhibiting the proliferation and metastasis of cancer cells.
  • EGFR-TKIs epidermal growth factor receptor-tyrosine kinase inhibitors
  • EGFR-TKIs epidermal growth factor receptor-tyrosine kinase inhibitors
  • EGFR-TKIs epidermal growth factor receptor-tyrosine kinase inhibitors
  • the object of the present invention is to provide a pharmaceutical composition, which can be used to treat lung cancer, and further can be used in combination with EGFR-TKIs to treat lung cancer with EGFR mutation and EGFR-TKIs resistance, and prolong The use cycle of EGFR-TKIs.
  • One aspect of the present invention provides the use of a pharmaceutical composition, which is used to prepare a drug for treating lung cancer, wherein the pharmaceutical composition comprises a nuclear protein kinase C- ⁇ inhibitor, and the nuclear protein kinase C- ⁇
  • the delta inhibitors are abecicini, albendazole, anmosanpine, ceritinib dihydrochloride, cobitinib, dabigatran etexilate, dabrafenib, infeetin, ingenia Alcohol, Esazomib, Midostaurin, Niclosamide, Nintedanib Ethionate, Ponatinib, Raloxifene, Regorafenib, Ruzotinib, Tafenol Quinoquine, travoprost, mitochondrial antioxidant, vortioxetine or derivatives of the above ingredients.
  • the pharmaceutical composition of the present invention can reduce the drug resistance of lung cancer cells to EGFR-TKIs by using nuclear protein kinase C- ⁇ inhibitors, so it is suitable for the preparation of drugs for the treatment of lung cancer, especially those with EGFR mutations and EGFR-TKIs. Drugs for TKIs-resistant lung cancer.
  • the concentration of the nuclear protein kinase C- ⁇ inhibitor may be 0.05 ⁇ M to 10 ⁇ M.
  • the pharmaceutical composition may further comprise an inhibitor of epidermal growth factor receptor-tyrosine kinase.
  • the concentration of the epidermal growth factor receptor-tyrosine kinase inhibitor can be 0.05 ⁇ M to 1 ⁇ M.
  • the epidermal growth factor receptor-tyrosine kinase inhibitor can be gefitinib.
  • nucleoprotein kinase C- ⁇ inhibitor can be nintedanib ethylsulfonate
  • concentration of nintedanib ethylsulfonate can be from 0.5 ⁇ M to 5 ⁇ M
  • concentration of the gefitinib can be 0.05 ⁇ M to 1 ⁇ M.
  • the concentration of the ponatinib can be 0.05 ⁇ M to 0.5 ⁇ M, and the gefitinib The concentration can be 0.05 ⁇ M to 1 ⁇ M.
  • the nuclear protein kinase C- ⁇ inhibitor can be regorafenib
  • the concentration of the regorafenib can be 1 ⁇ M to 10 ⁇ M
  • the concentration of the gefitinib can be It can be from 0.05 ⁇ M to 1 ⁇ M.
  • the nuclear protein kinase C- ⁇ inhibitor can be cobitinib
  • the concentration of the cobitinib can be 1 ⁇ M to 10 ⁇ M
  • the concentration of the gefitinib can be It can be from 0.05 ⁇ M to 1 ⁇ M.
  • the lung cancer can be non-small cell lung cancer.
  • the lung cancer may be resistant to epidermal growth factor receptor-tyrosine kinase inhibitors.
  • Figure 1 is a conjugate focal high-throughput screening system capable of measuring the amount of nuclear protein kinase C- ⁇ ;
  • Fig. 2A, Fig. 2B, Fig. 2C, Fig. 2D, Fig. 2E and Fig. 2F are respectively embodiment 1, embodiment 2,
  • Fig. 3 is the comparison diagram of the fluorescence intensity of the treated GR10 cells of Example 1 to Example 4, Comparative Example 1 and Comparative Example 2;
  • Fig. 4A, Fig. 4B, Fig. 4C and Fig. 4D are the relationship diagrams of cell viability and concentration after treatment of GR6 cells in Example 5, Example 6, Example 7 and Example 8 respectively;
  • FIG. 5A , FIG. 5B , FIG. 5C and FIG. 5D are graphs showing the relationship between cell survival rate and concentration of GR10 cells treated in Example 9, Example 10, Example 11 and Example 12, respectively.
  • the present invention provides the use of a pharmaceutical composition, which is used to prepare a drug for treating lung cancer, wherein the pharmaceutical composition comprises a nuclear protein kinase C- ⁇ (nuclear protein kinase C- ⁇ , nPKC ⁇ ) inhibitor, and the The nuclear protein kinase C- ⁇ inhibitors are abemaciclib, albendazole, amoxapine, ceritinib dihydrochloride, and cobitinib (cobimetinib), dabigatran etexilate, dabrafenib, emamectin, ingenol, ixazomib, midostaurin ), niclosamide, nintedanibesylate, ponatinib, raloxifene, regorafenib, razote Ruxolitinib, tafenoquine, travoprost, visomitin, vortioxetine or derivatives of the above
  • the concentration of the nuclear protein kinase C- ⁇ inhibitor of the pharmaceutical composition of the present invention may be 0.05 ⁇ M to 10 ⁇ M.
  • the pharmaceutical composition of the present invention may also comprise an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs), the epidermal growth factor receptor-tyrosine kinase inhibitor
  • EGFR-TKIs epidermal growth factor receptor-tyrosine kinase inhibitor
  • the concentration of the agent may be 0.05 ⁇ M to 1 ⁇ M
  • the epidermal growth factor receptor-tyrosine kinase inhibitor may be gefitinib.
  • nuclear protein kinase C- ⁇ inhibitor and epidermal growth factor receptor-tyrosine kinase inhibitor can be adjusted depending on the type.
  • the concentration of nintedanib ethylsulfonate can be 0.5 ⁇ M to 5 ⁇ M, and the concentration of gefitinib It can be from 0.05 ⁇ M to 1 ⁇ M.
  • the concentration of ponatinib may be 0.05 ⁇ M to 0.5 ⁇ M, and the concentration of gefitinib may be 0.05 ⁇ M to 1 ⁇ M.
  • the concentration of regorafenib may be 1 ⁇ M to 10 ⁇ M, and the concentration of gefitinib may be 0.05 ⁇ M to 1 ⁇ M.
  • the concentration of cobitinib may be 1 ⁇ M to 10 ⁇ M, and the concentration of gefitinib may be 0.05 ⁇ M to 1 ⁇ M.
  • the lung cancer treated by the pharmaceutical composition of the present invention may be non-small cell lung cancer.
  • the lung cancer treated by the pharmaceutical composition of the present invention may be resistant to epidermal growth factor receptor-tyrosine kinase inhibitors.
  • the nuclear protein kinase C- ⁇ inhibitor disclosed in the present invention can be verified by in vitro experiments, and it can inhibit the growth of non-small cell lung cancer cells resistant to epidermal growth factor receptor-tyrosine kinase inhibitors , and can be further verified by in vivo experiments that the nuclear protein kinase C- ⁇ inhibitor disclosed in the present invention can be administered to animals with lung cancer resistant to epidermal growth factor receptor-tyrosine kinase inhibitors (e.g. mouse models), and therapeutic effects can be obtained.
  • a positive result in one or more tests is sufficient to demonstrate the actual utility of the tested inhibitor and an appropriate dosage range and route of administration for animals (eg, humans) can be determined based on the test results.
  • Useful pharmaceutical dosage forms for administering the nucleoprotein kinase C-delta inhibitors of the invention include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injections, and oral suspensions.
  • the dosage administered will depend on factors including the age of the subject, the health and weight of the subject, the extent of the disease, the type of concomitant treatment (if any), the frequency of treatment and the nature of the desired effect.
  • the daily dose of active ingredient may vary, for example, 0.1 to 2000 mg per day, or 10-500 mg one or more times per day may be effective to obtain the desired results.
  • the same dosage form can generally be used when the nucleoprotein kinase C-delta inhibitors of the invention are administered stepwise or in combination with at least one other therapeutic agent.
  • the dosage form and route of administration should be selected based on the compatibility of the combined drugs. Therefore, "co-administration" in this specification should be understood to include the concomitant or sequential administration of at least two agents, or as a fixed-dose combination of at least two active ingredients.
  • nucleoprotein kinase C- ⁇ inhibitors of the present invention may be administered as the sole active ingredient, or in combination with at least one second active ingredient selected from, for example, those known to be useful in the treatment of patients with non-small cell lung cancer.
  • Other active ingredients especially epidermal growth factor receptor-tyrosine kinase inhibitors.
  • test examples are hereby used to further demonstrate the present invention, so that those with common knowledge in the technical field to which the present invention belongs can fully utilize and practice the present invention without excessive interpretation, and these test examples should not be regarded as To limit the scope of the invention, but to illustrate how to practice the materials and methods of the invention.
  • Figure 1 is a confocal-based high-content screening system that can measure the amount of nuclear protein kinase C- ⁇ .
  • this test example utilizes the method shown in Figure 1. The screening system shown was used to measure whether the nuclear protein kinase C- ⁇ inhibitor of the present invention can inhibit the production of nuclear protein kinase C- ⁇ in cancer cells.
  • gefitinib-resistant non-small cell lung cancer cells gefitinib-resistant10 cells, hereinafter referred to as GR10 cells
  • GR10 cells gefitinib-resistant10 cells
  • Examples 1 to 4 are respectively to GR10 cells with nintedanib ethyl sulfonate (hereinafter referred to as Nin), ponatinib (hereinafter referred to as Pon), regorafenib (hereinafter referred to as Reg) or corby
  • the amount of nuclear protein kinase C- ⁇ in GR10 cells was determined by conjugate focus high-throughput image analysis.
  • this test example additionally includes Comparative Example 1 and Comparative Example 2.
  • Comparative Example 1 is untreated GR10 cells
  • Comparative Example 2 is non-medical sotrastaurin (sotrastaurin, hereinafter referred to as Sotra) on GR10 cells. Cells are processed.
  • FIG. 2A to FIG. 2F and FIG. 3 Please refer to FIG. 2A to FIG. 2F and FIG. 3 .
  • Fig. 2A to Fig. 2F are respectively embodiment 1, embodiment 2,
  • Example 3 is the GR10 cells of Example 1 to Example 4, Comparative Example 1 and Comparative Example 2 after treatment
  • Figure 3 is the GR10 cells of Example 1 to Example 4, Comparative Example 1 and Comparative Example 2 after treatment
  • the nuclear protein kinase C- ⁇ inhibitor of the present invention can produce nuclear protein kinase C- ⁇ inhibitory effect on GR10 cells, And its inhibitory effect is no less than the inhibitory effect of non-medical sortastaurin (comparative example 2), and it can be known from Figure 3 that when the concentration of Nin is greater than 5 ⁇ M, the concentration of Pon is greater than 0.1 ⁇ M, and the concentration of Reg is greater than 5 ⁇ M Or when the concentration of Cob is greater than 5 ⁇ M, it can show good inhibitory ability of nuclear protein kinase C- ⁇ .
  • this test example comprises embodiment 5 to embodiment 12, and it is with different concentrations of nuclear protein kinase C- ⁇ inhibitor (Nin, Pon, Reg or Cob) and gefitinib (hereinafter referred to as Gef) GR6 cells or GR10 cells were treated, and the cell viability (cell viability) of each embodiment was measured after 3 days of treatment, and the cell types used in Examples 5 to 12, the types of nuclear protein kinase C- ⁇ inhibitors Please refer to Table 2 and Table 3 below for the concentration and Gef concentration.
  • nuclear protein kinase C- ⁇ inhibitor nuclear protein kinase C- ⁇ inhibitor
  • Gef gefitinib
  • Figure 4A to Figure 4D Please refer to Figure 4A to Figure 4D and Figure 5A to Figure 5D, Figure 4A to Figure 4D are respectively Embodiment 5,
  • FIG. 6 The relationship between the cell survival rate and the concentration of the GR6 cells in Example 6, Example 7 and Example 8 after treatment, Figure 5A to Figure 5D are respectively the results of Example 9, Example 10, Example 11 and Example 12 GR10 cells are treated cell viability and concentration diagram, wherein, the above-mentioned cell viability is obtained by MTT test, and the combination index (combination index, CI) of nuclear protein kinase C- ⁇ and Gef in each embodiment is calculated simultaneously. ) to understand whether nuclear protein kinase C- ⁇ and Gef can produce synergy.
  • CI combination index
  • the nuclear protein kinase C- ⁇ inhibitor of the present invention can reduce the cell survival rate of GR6 cells and GR10 cells, and after adding Gef, it can significantly reduce the GR6 Cell survival rate of cells and GR10 cells, and nuclear protein kinase C- ⁇ and Gef can produce obvious synergistic effect (CI ⁇ 1).
  • nuclear protein kinase C- ⁇ and Gef can produce a strong synergistic effect (CI ⁇ 0.3), which further reduces the cell survival rate of GR6 cells and GR10 cells.
  • the pharmaceutical composition of the present invention can reduce the drug resistance of lung cancer cells to EGFR-TKIs by using nuclear protein kinase C- ⁇ inhibitors, so it is suitable for the preparation of drugs for the treatment of lung cancer, especially those with EGFR mutations and those with Drugs for EGFR-TKIs-resistant lung cancer.

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Abstract

一种医药组合物治疗肺癌的用途，所述医药组合物包含一核蛋白激酶C-δ抑制剂，且所述核蛋白激酶C-δ抑制剂为阿贝西尼、阿苯达唑、安莫散平、双盐酸盐色瑞替尼、考比替尼、达比加群酯、达拉非尼、因灭汀、巨大戟醇、依萨佐米、米哚妥林、氯硝柳胺、尼达尼布乙基磺酸盐、普纳替尼、雷洛昔芬、瑞格菲尼、卢佐替尼、他非诺喹、曲伏前列素、粒线体抗氧化剂、沃替西汀或上述成分的衍生物。借此，所述医药组合物可用于制备治疗肺癌的药物。

Description

医药组合物治疗肺癌的用途 技术领域
本发明涉及一种医药组合物的用途，特别涉及一种包含核蛋白激酶C-δ抑制剂的医药组合物治疗肺癌的用途。
背景技术
肺癌一直是发生率及死亡率最高的癌症，在全世界的癌症人口中，约有20％为肺癌患者，且病患的五年存活率仅约15％。根据组织病理学，肺癌可大致分为非小细胞癌和小细胞癌，其中约85％～90％的肺癌属于非小细胞癌，且根据非小细胞癌侵犯的程度不同，可采取不同的治疗方法，较早期(第I期及第II期)的非小细胞癌可采取手术方式，将肿瘤完全切除，针对中晚期(第III期及第IV期)或无法接受手术的病患，可采取化学药物搭配放射治疗来获得较好的治疗效果。
除此之外，标靶治疗亦为非小细胞癌治疗的另一种选择。典型的临床标靶治疗用药为表皮生长因子受体－酪胺酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors，EGFR-TKIs)，其可结合于表皮生长因子受体(EGFR)上并阻断信息传递，进而达到抑制癌细胞增生及转移的效果。然而，临床上约50％的非小细胞癌病患皆带有EGFR基因突变，其癌细胞上的EGFR会过度表现，即便使用EGFR-TKIs进行治疗，仍极有机会于治疗后两年内复发，且病患会对EGFR-TKIs产生抗药性，导致复发后无适当药物可供进一步治疗。
有鉴于此，研发一种用于治疗具EGFR突变及具EGFR-TKIs抗药性的肺癌的药物仍为相关研究人员及业者努力的目标。
发明内容
为达成上述目标，本发明的目的在于提供一种医药组合物，其可用以治疗肺癌，进一步地可与EGFR-TKIs合并使用，以治疗具EGFR突变及具EGFR-TKIs抗药性的肺癌，并延长EGFR-TKIs的使用周期。
本发明的一态样提供一种医药组合物的用途，其是用于制备治疗肺癌的药 物，其中所述医药组合物包含一核蛋白激酶C-δ抑制剂，且所述核蛋白激酶C-δ抑制剂为阿贝西尼、阿苯达唑、安莫散平、双盐酸盐色瑞替尼、考比替尼、达比加群酯、达拉非尼、因灭汀、巨大戟醇、依萨佐米、米哚妥林、氯硝柳胺、尼达尼布乙基磺酸盐、普纳替尼、雷洛昔芬、瑞格菲尼、卢佐替尼、他非诺喹、曲伏前列素、粒线体抗氧化剂、沃替西汀或上述成分的衍生物。
据此，本发明的医药组合物通过使用核蛋白激酶C-δ抑制剂，可以降低肺癌细胞对EGFR-TKIs的抗药性，故适用于制备治疗肺癌的药物，特别是具EGFR突变及具EGFR-TKIs抗药性的肺癌的药物。
依据前述的医药组合物的用途，其中所述核蛋白激酶C-δ抑制剂的浓度可为0.05μM至10μM。
依据前述的医药组合物的用途，其中所述医药组合物还可包含一表皮生长因子受体－酪胺酸激酶抑制剂。
依据前述的医药组合物的用途，其中所述表皮生长因子受体－酪胺酸激酶抑制剂的浓度可为0.05μM至1μM。
依据前述的医药组合物的用途，其中所述表皮生长因子受体－酪胺酸激酶抑制剂可为吉非替尼。
依据前述的医药组合物的用途，其中所述核蛋白激酶C-δ抑制剂可为尼达尼布乙基磺酸盐，所述尼达尼布乙基磺酸盐的浓度可为0.5μM至5μM，且所述吉非替尼的浓度可为0.05μM至1μM。
依据前述的医药组合物的用途，其中所述核蛋白激酶C-δ抑制剂可为普纳替尼，所述普纳替尼的浓度可为0.05μM至0.5μM，且所述吉非替尼的浓度可为0.05μM至1μM。
依据前述的医药组合物的用途，其中所述核蛋白激酶C-δ抑制剂可为瑞格菲尼，所述瑞格菲尼的浓度可为1μM至10μM，且所述吉非替尼的浓度可为0.05μM至1μM。
依据前述的医药组合物的用途，其中所述核蛋白激酶C-δ抑制剂可为考比替尼，所述考比替尼的浓度可为1μM至10μM，且所述吉非替尼的浓度可为0.05μM至1μM。
依据前述的医药组合物的用途，其中所述肺癌可为非小细胞肺癌。
依据前述的医药组合物的用途，其中所述肺癌可对表皮生长因子受体－酪 胺酸激酶抑制剂具有耐药性。
附图说明
为让本发明的上述和其他目的、特征、优点与实施例能更明显易懂，所附附图的说明如下：
图1为可测量核蛋白激酶C-δ量的共轭焦高通量筛选系统；
图2A、图2B、图2C、图2D、图2E和图2F分别为实施例1、实施例2、
实施例3、实施例4、比较例1和比较例2的GR10细胞经处理后的免疫荧光染色图；
图3为实施例1至实施例4、比较例1及比较例2的GR10细胞经处理后的荧光强度比较图；
图4A、图4B、图4C和图4D分别为实施例5、实施例6、实施例7和实施例8的GR6细胞经处理后的细胞存活率与浓度的关系图；以及
图5A、图5B、图5C和图5D分别为实施例9、实施例10、实施例11和实施例12的GR10细胞经处理后的细胞存活率与浓度的关系图。
具体实施方式
本发明提供一种医药组合物的用途，其是用于制备治疗肺癌的药物，其中所述医药组合物包含一核蛋白激酶C-δ(nuclear protein kinase C-δ，nPKCδ)抑制剂，且所述核蛋白激酶C-δ抑制剂为阿贝西尼(abemaciclib)、阿苯达唑(albendazole)、安莫散平(amoxapine)、双盐酸盐色瑞替尼(ceritinibdihydrochloride)、考比替尼(cobimetinib)、达比加群酯(dabigatran etexilate)、达拉非尼(dabrafenib)、因灭汀(emamectin)、巨大戟醇(ingenol)、依萨佐米(ixazomib)、米哚妥林(midostaurin)、氯硝柳胺(niclosamide)、尼达尼布乙基磺酸盐(nintedanibesylate)、普纳替尼(ponatinib)、雷洛昔芬(raloxifene)、瑞格菲尼(regorafenib)、卢佐替尼(ruxolitinib)、他非诺喹(tafenoquine)、曲伏前列素(travoprost)、粒线体抗氧化剂(visomitin)、沃替西汀(vortioxetine)或上述成分的衍生物。
本发明的医药组合物的核蛋白激酶C-δ抑制剂的浓度可为0.05μM至10μM。本发明的医药组合物还可包含一表皮生长因子受体－酪胺酸激酶抑制剂 (epidermal growth factor receptor-tyrosine kinase inhibitors，EGFR-TKIs)，所述表皮生长因子受体－酪胺酸激酶抑制剂的浓度可为0.05μM至1μM，且所述表皮生长因子受体－酪胺酸激酶抑制剂可为吉非替尼(gefitinib)。
需特别留意的是，核蛋白激酶C-δ抑制剂与表皮生长因子受体－酪胺酸激酶抑制剂的浓度可以视其种类而调整。
举例而言，当核蛋白激酶C-δ抑制剂为尼达尼布乙基磺酸盐时，尼达尼布乙基磺酸盐的浓度可为0.5μM至5μM，且吉非替尼的浓度可为0.05μM至1μM。当核蛋白激酶C-δ抑制剂为普纳替尼时，普纳替尼的浓度可为0.05μM至0.5μM，且吉非替尼的浓度可为0.05μM至1μM。当核蛋白激酶C-δ抑制剂为瑞格菲尼时，瑞格菲尼的浓度可为1μM至10μM，且吉非替尼的浓度可为0.05μM至1μM。当核蛋白激酶C-δ抑制剂为考比替尼时，考比替尼的浓度可为1μM至10μM，且吉非替尼的浓度可为0.05μM至1μM。
本发明的医药组合物用以治疗的肺癌可为非小细胞肺癌，此外，本发明的医药组合物用以治疗的肺癌可对表皮生长因子受体－酪胺酸激酶抑制剂具有耐药性。
除非另有说明，本说明书中所使用的所有专门术语、符号、其他科学名词或术语具有本发明所属领域中熟谙此技艺者习知的含意，除非使用它们的上下文另有说明。在某些情况下，具有习知含意的术语是在本文中界定以达到明确及/或实时参考的目的，且本说明书中所纳入的这些定义应被解释为不一定与本领域中习知的意义有实质差异。本文中所叙述或引用的许多技术与程序均为大众所习知且时常为本领域中的技术人员以常规方法使用。在适当情况下，除非另有说明，市售套组和试剂的使用程序一般均根据制造商界定的使用说明及/或参数来进行。
本发明揭示的核蛋白激酶C-δ抑制剂可以通过体外(in vitro)试验验证，其可抑制对表皮生长因子受体－酪胺酸激酶抑制剂具有耐药性的非小细胞肺癌细胞的生长，并可进一步通过体内(in vivo)试验验证，本发明揭示的核蛋白激酶C-δ抑制剂可以施用于患有对表皮生长因子受体－酪胺酸激酶抑制剂具耐药性肺癌的动物(例如小鼠模型)，且可获得治疗效果。在一个或多个测试中的阳性结果足以证明所测试的抑制剂的实际效用，且可基于试验结果确定动物(例如人)的合适剂量范围和给药途径。
用于施用本发明的核蛋白激酶C-δ抑制剂的有用药物剂型，包含但不限于硬和软明胶胶囊、片剂、肠胃外注射剂和口服混悬剂。施用剂量的取决因素包含受试者的年龄、受试者的健康和体重、疾病的程度、同时治疗的类型(若有)、治疗频率和所需效果的性质。通常活性成分的每日剂量可以为非定量，例如，每天0.1至2000毫克，或每天一次或多次10-500毫克可有效获得所需结果。
当本发明的核蛋白激酶C-δ抑制剂逐步给药或与至少一种其它治疗剂联合给药时，通常可以使用相同的剂型。当药物以物理组合给药时，应根据组合药物的兼容性选择剂型和给药途径。因此，本说明书所述的「共同给药」应理解为包含伴随或顺序给予至少两种药剂，或者作为至少两种活性组分的固定剂量组合。
本发明的核蛋白激酶C-δ抑制剂可以作为唯一的活性成分，或与至少一种第二活性成分组合施用，所述第二活性成分选自例如已知可用于治疗非小细胞肺癌患者的其他活性成分，特别是表皮生长因子受体－酪胺酸激酶抑制剂。
兹以下列具体试验例进一步示范说明本发明，用以有利于本发明所属技术领域的公知常识者，可在不需过度解读的情形下完整利用并实践本发明，而不应将这些试验例视为对本发明范围的限制，但用于说明如何实施本发明的材料及方法。
＜核蛋白激酶C-δ抑制剂对具表皮生长因子受体－酪胺酸激酶抑制剂耐药性的非小细胞肺癌细胞的抑制作用＞
请参照图1，图1为可测量核蛋白激酶C-δ量的共轭焦高通量筛选系统(confocal-based high-content screening system)。为得知本发明的核蛋白激酶C-δ抑制剂对具表皮生长因子受体－酪胺酸激酶抑制剂耐药性的非小细胞肺癌细胞的抑制生长作用，本试验例利用如图1所示的筛选系统，来测量本发明的核蛋白激酶C-δ抑制剂是否能抑制癌细胞中的核蛋白激酶C-δ产生。
本试验例选用具吉非替尼抗药性的非小细胞肺癌细胞(gefitinib-resistant10cells，以下简称GR10细胞)作为细胞模型。实施例1至实施例4是分别对GR10细胞以尼达尼布乙基磺酸盐(以下简称Nin)、普纳替尼(以下简称Pon)、瑞格菲尼(以下简称Reg)或考比替尼(以下简称Cob)经24小时处理后，利用共轭焦高通量影像分析来判定GR10细胞内的核蛋白激酶C-δ量。另一方面，本试验例另包含比较例1及比较例2，比较例1是未经处理的GR10细胞， 而比较例2是以非医用的索塔妥林(sotrastaurin，以下简称Sotra)对GR10细胞进行处理。
实施例1至实施例4、比较例1及比较例2所使用的核蛋白激酶C-δ抑制剂种类与浓度请参照下表1。
Figure PCTCN2022096233-appb-000001
请参照图2A至图2F及图3。图2A至图2F分别为实施例1、实施例2、
实施例3、实施例4、比较例1和比较例2的GR10细胞经处理后的免疫荧光染色图，图3为实施例1至实施例4、比较例1及比较例2的GR10细胞经处理后的荧光强度比较图，其中，图2A至图2F中的细胞颜色越浅(越接近白色)代表核蛋白激酶C-δ的浓度越高。
由图2A至图2F可以看出，相较于未经处理的GR10细胞(比较例1)，本发明的核蛋白激酶C-δ抑制剂对GR10细胞可以产生核蛋白激酶C-δ抑制性，且其抑制效果不亚于非医用的索塔妥林的抑制效果(比较例2)，且由图3可以得知，当Nin的浓度大于5μM、Pon的浓度大于0.1μM、Reg的浓度大于5μM或Cob的浓度大于5μM时，即能表现出良好的核蛋白激酶C-δ抑制能力。
＜核蛋白激酶C-δ抑制剂与表皮生长因子受体－酪胺酸激酶抑制剂共同对具表皮生长因子受体－酪胺酸激酶抑制剂耐药性的非小细胞肺癌细胞的抑制生长作用＞
本试验例选用前一试验例的GR10细胞以及GR6细胞进行以下实验。简言之，本试验例包含实施例5至实施例12，其是以不同浓度的核蛋白激酶C-δ抑制剂(Nin、Pon、Reg或Cob)与吉非替尼(以下简称Gef)共同对GR6细胞或GR10细胞进行处理，并于处理3日后测定各实施例的细胞存活率(cell viability)，而实施例5至实施例12所使用的细胞种类、核蛋白激酶C-δ抑制剂种类与浓度以及Gef浓度请参照下表2及下表3。
Figure PCTCN2022096233-appb-000002
Figure PCTCN2022096233-appb-000003
请参照图4A至图4D以及图5A至图5D，图4A至图4D分别为实施例5、
实施例6、实施例7和实施例8的GR6细胞经处理后的细胞存活率与浓度的关系图，图5A至图5D分别为实施例9、实施例10、实施例11和实施例12的GR10细胞经处理后的细胞存活率与浓度的关系图，其中，上述细胞存活率是以MTT试验而得，同时计算出各实施例中核蛋白激酶C-δ与Gef的合并指数(combination index，CI)以了解核蛋白激酶C-δ与Gef是否能产生协同作用(synergy)。
由图4A至图4D及图5A至图5D可以得知，本发明的核蛋白激酶C-δ抑制剂均能降低GR6细胞及GR10细胞的细胞存活率，在加入Gef之后，更能大幅降低GR6细胞及GR10细胞的细胞存活率，且核蛋白激酶C-δ与Gef能产生明显的协同作用(CI<1)。此外，于特定浓度下，核蛋白激酶C-δ与Gef能产生强协同作用(CI<0.3)，更进一步降低了GR6细胞及GR10细胞的细胞存活率。
综上所述，本发明的医药组合物通过使用核蛋白激酶C-δ抑制剂，可以降低肺癌细胞对EGFR-TKIs的抗药性，故适用于制备治疗肺癌的药物，特别是具EGFR突变及具EGFR-TKIs抗药性的肺癌的药物。
虽然本发明已以实施方式揭露如上，然其并非用以限定本发明，任何熟习此技艺者，在不脱离本发明的精神和范围内，当可作各种的更动与润饰，因此本发明的保护范围当视后附的权利要求所界定者为准。

Claims (11)

  1. 一种医药组合物的用途，其是用于制备治疗肺癌的药物，其特征在于，所述医药组合物包含一核蛋白激酶C-δ(nuclear protein kinase C-δ，nPKCδ)抑制剂；
    其中，所述核蛋白激酶C-δ抑制剂为阿贝西尼(abemaciclib)、阿苯达唑(albendazole)、安莫散平(amoxapine)、双盐酸盐色瑞替尼(ceritinibdihydrochloride)、考比替尼(cobimetinib)、达比加群酯(dabigatran etexilate)、达拉非尼(dabrafenib)、因灭汀(emamectin)、巨大戟醇(ingenol)、依萨佐米(ixazomib)、米哚妥林(midostaurin)、氯硝柳胺(niclosamide)、尼达尼布乙基磺酸盐(nintedanibesylate)、普纳替尼(ponatinib)、雷洛昔芬(raloxifene)、瑞格菲尼(regorafenib)、卢佐替尼(ruxolitinib)、他非诺喹(tafenoquine)、曲伏前列素(travoprost)、粒线体抗氧化剂(visomitin)、沃替西汀(vortioxetine)或上述成分的衍生物。
  2. 如权利要求1所述的医药组合物的用途，其特征在于，所述核蛋白激酶C-δ抑制剂的浓度为0.05μM至10μM。
  3. 如权利要求1所述的医药组合物的用途，其特征在于，所述医药组合物还包含一表皮生长因子受体－酪胺酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors，EGFR-TKIs)。
  4. 如权利要求3所述的医药组合物的用途，其特征在于，所述表皮生长因子受体－酪胺酸激酶抑制剂的浓度为0.05μM至1μM。
  5. 如权利要求3所述的医药组合物的用途，其特征在于，所述表皮生长因子受体－酪胺酸激酶抑制剂为吉非替尼(gefitinib)。
  6. 如权利要求5所述的医药组合物的用途，其特征在于，所述核蛋白激酶C-δ抑制剂为尼达尼布乙基磺酸盐，所述尼达尼布乙基磺酸盐的浓度为0.5μM至5μM，且所述吉非替尼的浓度为0.05μM至1μM。
  7. 如权利要求5所述的医药组合物的用途，其特征在于，所述核蛋白激酶C-δ抑制剂为普纳替尼，所述普纳替尼的浓度为0.05μM至0.5μM，且所述吉非替尼的浓度为0.05μM至1μM。
  8. 如权利要求5所述的医药组合物的用途，其特征在于，所述核蛋白激酶C-δ抑制剂为瑞格菲尼，所述瑞格菲尼的浓度为1μM至10μM，且所述吉非替尼的浓度为0.05μM至1μM。
  9. 如权利要求5所述的医药组合物的用途，其特征在于，所述核蛋白激酶C-δ抑制剂为考比替尼，所述考比替尼的浓度为1μM至10μM，且所述吉非替尼的浓度为0.05μM至1μM。
  10. 如权利要求1所述的医药组合物的用途，其特征在于，所述肺癌为非小细胞肺癌。
  11. 如权利要求1所述的医药组合物的用途，其特征在于，所述肺癌对表皮生长因子受体－酪胺酸激酶抑制剂具有耐药性。
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