WO2023193705A1 - Use of chiauranib in resisting pancreatic cancer - Google Patents

Use of chiauranib in resisting pancreatic cancer Download PDF

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WO2023193705A1
WO2023193705A1 PCT/CN2023/086165 CN2023086165W WO2023193705A1 WO 2023193705 A1 WO2023193705 A1 WO 2023193705A1 CN 2023086165 W CN2023086165 W CN 2023086165W WO 2023193705 A1 WO2023193705 A1 WO 2023193705A1
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derivatives
pancreatic cancer
inhibitor
pnd1186
chidamide
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PCT/CN2023/086165
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French (fr)
Chinese (zh)
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黄圣健
毛旭华
熊秋韵
潘德思
鲁先平
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深圳微芯生物科技股份有限公司
成都微芯药业有限公司
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Publication of WO2023193705A1 publication Critical patent/WO2023193705A1/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
    • A61K31/435—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
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • 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 present invention relates to the field of pharmaceutical applications, and in particular to the new use of Siorani in the preparation of medicines for treating pancreatic cancer.
  • Pancreatic cancer is a malignant tumor that occurs in the exocrine pancreatic gland.
  • Pancreatic malignant tumors can originate from pancreatic exocrine glands, endocrine glands or non-epithelial tissues, 95% of which are pancreatic cancer.
  • This disease has the worst prognosis and has high morbidity and mortality. It mainly uses drugs, surgery, radiotherapy and chemotherapy to treat diseases.
  • the main treatment for pancreatic cancer is surgical resection, and palliative short-circuit surgery, chemotherapy and radiotherapy are often used for those who are inoperable.
  • chemotherapy drugs include gemcitabine, 5-fluorouracil, cisplatin, Taxotere, platinum oxalate, Avastin, capecitabine, etc.
  • Ciaroni is a new protein kinase inhibitor with complete intellectual property rights independently developed by Shenzhen Microchip Biotechnology Co., Ltd.
  • Scioronib is a small molecule anti-tumor targeted drug targeting multiple protein kinases. It has anti-tumor angiogenesis through its high selective inhibitory activity on VEGFR/PDGFR/c-Kit, Aurora B, and CSF-1R targets. It exerts a comprehensive anti-tumor effect through a three-pathway anti-tumor synergistic mechanism, including inhibiting tumor cell mitosis and regulating the tumor inflammatory microenvironment.
  • Cioranib's inhibitory activity on the key mitotic enzyme Aurora B is unique and has potential It can reduce the genomic instability of tumor tissue and inhibit the metastasis of tumor cells.
  • Scioronib exerts anti-tumor activity through three complementary mechanisms of inhibiting tumor angiogenesis, cell mitosis and tumor inflammatory microenvironment. At the same time, its high target selectivity also reduces the risk of side effects caused by off-target effects.
  • CN200910223861.5 discloses Sioroni compounds, which specifically discloses a naphthylamide derivative, its preparation method and application. This type of compound has both protein kinase inhibitory activity and histone deacetylase inhibitory activity, and can be used to treat diseases related to abnormal protein kinase activity or abnormal histone deacetylase activity, including inflammation, autoimmune diseases, and cancer. , neurological and neurodegenerative diseases, cardiovascular diseases, metabolic diseases, allergies, asthma and hormone-related diseases.
  • CN201610856945.2 discloses unsolvated crystals A, B, and C of cealoni and their preparation methods. It also relates to pharmaceutical compositions containing the crystals, and the preparation of the crystals for the treatment of protein steroid hormones. Application in drugs for diseases related to abnormal enzyme activity or abnormal histone deacetylase activity.
  • the object of the present invention is to provide the use of cealoni or its derivatives in the preparation of medicaments for preventing and/or improving and/or treating pancreatic cancer.
  • the cioronil derivatives include pharmaceutically acceptable salts, unsolvated crystals A, B or C thereof.
  • Unsolvated crystals A, B and C of Sioronil are disclosed in CN201610856945.2, the entire content of which is incorporated into the present invention.
  • the unit dosage of ceoranib or its derivatives is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
  • the present invention also provides the use of cearoni or its derivatives in combination with an HDAC inhibitor in the preparation of medicaments for preventing and/or improving and/or treating pancreatic cancer.
  • the cioronil derivatives include pharmaceutically acceptable salts, unsolvated crystals A, B or C thereof.
  • Unsolvated crystals A, B and C of Sioronil are disclosed in CN201610856945.2, the entire content of which is incorporated into the present invention.
  • the HDAC inhibitor is selected from the group consisting of Entinostat, Vorinostat, Panobinostat, Mocetinostat, and Belinostat. , Pracinostat, Romidepsin, Chidamide, or derivatives thereof.
  • the HDAC inhibitor is selected from chidamide or its derivatives.
  • the chidamide derivative includes its pharmaceutically acceptable salt, enantiomer, crystal form A or crystal form B.
  • CN201210489178.8 discloses the crystalline form A and crystalline form B of chidamide
  • CN201410136761.X discloses the enantiomers of chidamide, which are fully incorporated into the present invention.
  • the unit dosage of ceoranib or its derivatives is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
  • the unit dose of chidamide or its derivative is 5-100 mg. Preferably it is 5-60 mg. More preferably, it is 5 mg.
  • the present invention also provides the use of cealoni or its derivatives in combination with FAK inhibitors in the preparation of medicaments for preventing and/or improving and/or treating pancreatic cancer.
  • the cioronil derivatives include pharmaceutically acceptable salts, unsolvated crystals A, B or C thereof.
  • Unsolvated crystals A, B and C of Sioronil are disclosed in CN201610856945.2, the entire content of which is incorporated into the present invention.
  • the FAK inhibitor is selected from PND1186, GSK-2256098, TAE226, PF-562271, PF-431396, PF-04554878, and BI-4464.
  • the FAK inhibitor is selected from PND1186.
  • the unit dosage of ceoranib or its derivatives is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
  • the unit dose of PND1186 is 10-200 mg. Preferably it is 20-200 mg. More preferably, it is 200 mg.
  • the present invention also provides cealoni or its derivatives for preventing and/or improving and/or treating pancreatic cancer.
  • the cioronil derivatives include pharmaceutically acceptable salts, unsolvated crystals A, B or C thereof.
  • Unsolvated crystals A, B and C of Sioronil are disclosed in CN201610856945.2, the entire content of which is incorporated into the present invention.
  • the unit dosage of ceoranib or its derivatives is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
  • the present invention also provides ceopronil or its derivatives combined with HDAC inhibitors for preventing and/or improving and/or treating pancreatic cancer.
  • the cioronil derivatives include pharmaceutically acceptable salts, unsolvated crystals A, B or C thereof.
  • Unsolvated crystals A, B and C of Sioronil are disclosed in CN201610856945.2, the entire content of which is incorporated into the present invention.
  • the HDAC inhibitor is selected from the group consisting of Entinostat, Vorinostat, Panobinostat, Mocetinostat, and Belinostat. , Pracinostat, Romidepsin, Chidamide, or derivatives thereof.
  • the HDAC inhibitor is selected from chidamide or its derivatives.
  • the chidamide derivative includes its pharmaceutically acceptable salt, enantiomer, crystal form A or crystal form B.
  • CN201210489178.8 discloses the crystalline form A and crystalline form B of chidamide
  • CN201410136761.X discloses the enantiomers of chidamide, which are fully incorporated into the present invention.
  • the unit dosage of ceoranib or its derivatives is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
  • the unit dose of chidamide or its derivative is 5-100 mg. Preferably it is 5-60 mg. More preferably, it is 5 mg.
  • the present invention also provides ceoronil or a derivative thereof combined with a FAK inhibitor for preventing and/or improving and/or treating pancreatic cancer.
  • the cioronil derivatives include pharmaceutically acceptable salts, unsolvated crystals A, B or C thereof.
  • Unsolvated crystals A, B and C of Sioronil are disclosed in CN201610856945.2, the entire content of which is incorporated into the present invention.
  • the FAK inhibitor is selected from PND1186, GSK-2256098, TAE226, PF-562271, PF-431396, PF-04554878, and BI-4464.
  • the FAK inhibitor is selected from PND1186.
  • the unit dosage of ceoranib or its derivatives is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
  • the unit dose of PND1186 is 10-200 mg. Preferably it is 20-200 mg. More preferably, it is 200 mg.
  • the present invention also provides a pharmaceutical composition, which includes cealanib or its derivatives and a FAK inhibitor as active ingredients, as well as pharmaceutically acceptable excipients.
  • the FAK inhibitor is selected from PND1186, GSK-2256098, TAE226, PF-562271, PF-431396, PF-04554878, and BI-4464.
  • the FAK inhibitor is PND1186.
  • the unit dose of ceoranib or its derivative is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
  • the unit dose of PND1186 is 10-200 mg. Preferably it is 20-200mg. More preferably, it is 200 mg.
  • the present invention also provides a pharmaceutical kit, which includes the above-mentioned pharmaceutical composition.
  • the ceopronib or its derivatives and the FAK inhibitor are unit preparations with the same or different specifications, and the ceopronib or its derivative and the FAK inhibitor are placed in the same container. , or placed in different containers.
  • the present invention also provides methods for preventing and/or improving and/or treating pancreatic cancer by administering them to patients in need.
  • the cioronil derivative includes its pharmaceutically acceptable salt, unsolvated crystal A, B or C.
  • the HDAC inhibitor is selected from the group consisting of Entinostat, Vorinostat, Panobinostat, Mocetinostat, and Belinostat. , Pracinostat, Romidepsin, Chidamide, or derivatives thereof.
  • the HDAC inhibitor is selected from chidamide or its derivatives
  • the FAK inhibitor is selected from PND1186, GSK-2256098, TAE226, PF-562271, PF-431396, PF-04554878, and BI-4464.
  • the FAK inhibitor is PND1186
  • the unit dose of ceoranib or its derivative is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
  • the cioronil derivative includes its pharmaceutically acceptable salt, unsolvated crystal A, B or C.
  • Unsolvated crystals A, B and C of Sioronil are disclosed in CN201610856945.2, the entire content of which is incorporated into the present invention.
  • the unit dose of chidamide or its derivative is 5-100 mg. Preferably it is 5-60 mg. More preferably, it is 5 mg.
  • the chidamide derivative includes its pharmaceutically acceptable salt, enantiomer, crystal form A or crystal form B.
  • CN201210489178.8 discloses the crystalline form A and crystalline form B of chidamide
  • CN201410136761.X discloses the enantiomers of chidamide, which are fully incorporated into the present invention.
  • the unit dose of PND1186 is 10-200 mg. Preferably it is 20-200 mg. More preferably, it is 200 mg.
  • the invention has significant effects on the treatment of pancreatic cancer, including ceopronib alone, ceopronib combined with an HDAC inhibitor, and ceopronib combined with a FAK inhibitor, and provides a better choice for the treatment of pancreatic cancer. .
  • Figure 1 Tumor volume changes of different groups of pancreatic cancer PDX model mice in Example 1;
  • Figure 3 Changes in tumor weight of different groups of pancreatic cancer PDX model mice in Example 1; G1: Vehicle group; G2: Sioroni group; Note: Independent sample T test is used, vs G1*: P ⁇ 0.05,* *: P ⁇ 0.01,***: P ⁇ 0.001;
  • Figure 5 Tumor volume changes in different groups of pancreatic cancer PDX model mice in Example 2;
  • Figure 6 End-point tumor photos of different groups of pancreatic cancer PDX model mice in Example 2;
  • Figure 7 Changes in tumor weight of different groups of pancreatic cancer PDX model mice in Example 2; G3: Vehicle group; G4: Sciorone group; Note: Independent sample T test is used, vs G3*: P ⁇ 0.05,* *: P ⁇ 0.01,***: P ⁇ 0.001;
  • Figure 9 Changes in tumor weight of mPA KPC pancreatic cancer model in different groups of mice in situ pancreatic inoculation in Example 3;
  • G1 Vehicle group;
  • G2 Ciopronib group;
  • G3 PND1186 group;
  • G4 Ciopronib+ PND1186 combination group;
  • vs G1* P ⁇ 0.05, **: P ⁇ 0.01, ***: P ⁇ 0.001;
  • Figure 12 Tumor volume changes (fluorescence intensity) in the mPA KPC -luciferase pancreatic cancer model of orthotopic pancreatic inoculation of different groups of mice in Example 4;
  • Figure 13 Body weight changes in the mPA KPC -luciferase pancreatic cancer model of orthotopic pancreatic inoculation of different groups of mice in Example 4.
  • the present invention discloses the therapeutic use of Sioronil for pancreatic cancer. Persons skilled in the art can learn from the content of this article and make appropriate improvements and implementations. It should be noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are deemed to be included in the present invention.
  • the applications described in the present invention have been described through preferred embodiments. Relevant personnel can obviously make changes or appropriate changes and combinations to the applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention. .
  • the pancreatic cancer PDX model number B00329 is the tail of the pancreas, and the PDX model is from Jicui Yaokang Biological Co., Ltd.
  • the dosage volume is adjusted according to the mouse body weight, 10 ⁇ L/g ⁇ mouse body weight (g).
  • Vehicle group (model group): 0.5% CMC+0.1% Tween80;
  • Scioronil group The corresponding mass of Xioronil was added to the same solvent as the Vehicle group, and vortexed to form a suspension with a concentration of 1 mg/mL.
  • mice in each group were weighed on D3, D7, D10, D14, D17, and D21, the tumor volume was measured, and TGI TV was calculated.
  • the calculation formula is as follows:
  • V nt Tumor volume of mouse numbered n on day t
  • V n0 Tumor volume of mouse number n on day 0
  • RTV n relative tumor volume of mouse numbered n on day t
  • TGI TW tumor weight inhibition rate
  • meanTWtreat the average tumor weight of mice in the drug group at the end of treatment
  • meanTW vehicle the average tumor weight of mice in the Vehicle group at the end of treatment
  • the tumor volume of the PDX model increased over time, and the tumor growth rate in the Cioranib administration group was significantly lower than that in the control group.
  • Table 2 on D10, D14, D17, and D21, compared with the control group (vehicle), the tumor volume of the Cioranib group was significantly reduced, with a significant difference on D10 (P ⁇ 0.05), and on D14 There was a significant difference on D17 and D21 (P ⁇ 0.01), and there was a highly significant difference on D17 and D21 (P ⁇ 0.001).
  • the above data demonstrate that Sioronib can significantly inhibit the growth of PDX tumors.
  • the tumor size in the control group was relatively uniform, with a weight of approximately 0.31g.
  • the TGI TW of the end point was 57.58%.
  • Scioronib alone can significantly inhibit tumor growth and reduce tumor weight in the PDX model, without significant impact on animal body weight.
  • the pancreatic cancer PDX model number B00455 is the tail of the pancreas, and the PDX model is from Jicui Yaokang Biological Co., Ltd.
  • the day of grouping was defined as day 0 (D0), and administration started from D0.
  • the dosage is shown in Table 3.
  • Vehicle group (model group): 0.5% CMC+0.1% Tween80;
  • Scioronil group The corresponding mass of Xioronil was added to the same solvent as the Vehicle group, and vortexed to form a suspension with a concentration of 1 mg/mL.
  • mice in each group were weighed on D2, D5, D7, D12, D16, D19, and D22, tumor volume was measured, and TGI TV (tumor volume inhibition rate) was calculated.
  • the experimental end point was D22.
  • V nt Tumor volume of mouse numbered n on day t
  • V n0 Tumor volume of mouse number n on day 0
  • RTV n relative tumor volume of mouse numbered n on day t
  • the tumor volume of the PDX model increased over time, and the tumor growth rate in the Cioranib administration group was significantly lower than that in the control group.
  • the tumor volume of the Ciorani group As shown in Table 4, on D12, D16, D19, and D22, compared with the Vehicle group (G3), the tumor volume of the Ciorani group (G4) was significantly reduced, and there was a significant difference on D12 (P ⁇ 0.01 ), with extremely significant differences on D16, D19 and D22 (P ⁇ 0.001). Tips from Siolo Nico to significantly inhibit tumor growth.
  • TGI TV tumor volume inhibition rate
  • the tumor size in the control group was relatively uniform, with a weight of approximately 0.83g.
  • the TGI TW of the end point was 54.20%.
  • Scioronib alone can significantly inhibit tumor growth and reduce tumor weight in the PDX model, without significant impact on animal body weight.
  • the mPA KPC orthotopic spontaneous pancreatic cancer model is a tumor model formed by mutating KRAS (G12D) and TP53 in mice.
  • the tumor mass is isolated and re-transplanted orthotopically into the mouse pancreas to form a tumor model and used for drug efficacy research.
  • Animal source Jicui Yaokang Biological Co., Ltd.
  • mice Forty C57BL/6 female mice aged 5 to 6 weeks were inoculated into the pancreas in situ with mPA KPC tumor blocks (Jicui Yaokang Biological Co., Ltd.). The size of the inoculated tumor blocks was 2mm*2mm*2mm/mouse. Grouping will be carried out on the 6th day after vaccination, G1 Vehicle group, G2 Scioronib group, G3PND1186 group (PND1186 was purchased from Shanghai Loulan Biotechnology Co., Ltd.), G4 Scioronib + PND1186 combination group, and the groups will be defined on the day is day 0 (D0). Administration was started from D0, and the dosage was shown in Table 5.
  • Vehicle group (model group): 0.5% CMC+0.1% Tween80;
  • Scioronil group The corresponding mass of Xioronil was added to the same solvent as the Vehicle group, and vortexed to form two suspensions with concentrations of 0.5 mg/mL and 1 mg/mL;
  • PND1186 Add the corresponding mass of PND1186 to the same solvent as the Vehicle group, and vortex to form two suspensions with concentrations of 3mg/mL and 6mg/mL.
  • meanTWtreat the average tumor weight of mice in the drug group at the end of treatment
  • meanTW vehicle the average tumor weight of mice in the Vehicle group at the end of treatment
  • the tumor weight of the Ciopronib group (G2), PND1186 group (G3) and Ciopronib + PND1186 combination group (G4) was significantly reduced.
  • the G3 group has a significant difference (P ⁇ 0.01), and the G2 and G4 groups have a highly significant difference (P ⁇ 0.001).
  • the tumor suppressive effect of the G4 combination group was better than that of Cioranib and PND1186 alone, suggesting that the combination has better tumor suppressive advantages.
  • TGI TW tumor inhibition rate
  • both Sioronil and PND1186 tended to slightly reduce the animal body weight, but the weight reduction was not significant.
  • the animal body weight in the combined administration group was not significantly lower than that of the single drug group, indicating that the toxic and side effects of combined administration were no greater than those of the single drug group.
  • the drug group was more serious.
  • the single drug Ciaroni and the FAK inhibitor PND1186 can significantly inhibit the tumor growth of orthotopic pancreatic cancer in mice, while the combined administration has a better tumor inhibitory effect than the two single drugs, and has no significant impact on the animal body weight.
  • the mPA KPC orthotopic spontaneous pancreatic cancer model is a tumor model formed by mutating KRAS (G12D) and TP53 in mice.
  • the isolated tumor tissue was cultured as a single cell and a cell line was formed in vitro.
  • the cell line was labeled with green luciferase and mixed with matrix collagen and transplanted into the mouse pancreatic tissue to form an orthotopic tumor.
  • the imaging system detects tumor size in animals and is used for drug efficacy studies.
  • Animal source Jicui Yaokang Biological Co., Ltd.
  • mice 60 C57BL/6 female mice aged 6 to 7 weeks were inoculated into the pancreas in situ with mPA KPC -luciferase cells (Jicui Yaokang Biological Co., Ltd.), and the inoculation dose was 5 ⁇ 10 5 cells/100 ⁇ L/mouse (tumor cells and Matrigel According to the volume ratio of 4:1).
  • In vivo imaging was performed on the 6th day after inoculation. According to the imaging results, 40 mice were selected and divided into 4 groups: G1 Vehicle group, G2 Ciopronib group, G3 Chidamide group, and G4 Ciopronib + Chidamide. Amine combined group, and the day of grouping was defined as day 0 (D0). Administration was started from D0, and the dosage was shown in Table 7.
  • the dosing volume of a single drug is adjusted according to body weight, 10 ⁇ L/g ⁇ mouse body weight (g); when two drugs are administered jointly, the drugs cannot be mixed together, the dosing time interval is half an hour, and the total dosing volume is 10 ⁇ L/g. ⁇ Mouse body weight (g), the concentration of each drug preparation is doubled.
  • Vehicle group (model group): 0.5% CMC+0.1% Tween80;
  • Scioronil group The corresponding mass of Xioronil was added to the same solvent as the Vehicle group, and vortexed to form two suspensions with concentrations of 0.5 mg/mL and 1 mg/mL;
  • Chidamide The solvent is 0.2% CMC. Add the corresponding mass of chidamide into the solvent and vortex to form two suspensions with concentrations of 2 mg/mL and 4 mg/mL.
  • mice After administration, the mice were weighed on D3, D7, D10, and D14; on D7 and D14, the tumor volume was detected using a small animal live imager, the fluorescence value was recorded, and TGI TV (tumor fluorescence value inhibition rate) was calculated.
  • V nt Tumor volume of mouse numbered n on day t
  • V n0 Tumor volume of mouse number n on day 0
  • RTV n relative tumor volume of mouse numbered n on day t
  • the body weight of the animals decreased slightly during the administration, but it did not reach a significant level ( ⁇ 0.5%), nor did it affect the animal's activity state. Whether administered alone or in combination, the body weight of the animals was within the normal range without significant decrease, indicating that the drug dose was within the tolerance range of the animals.
  • Ciopronib and chidamide alone can significantly inhibit the tumor growth of orthotopic pancreatic cancer in mice, while combined administration has a better tumor inhibitory effect than the two single drugs without significant impact on the animal body weight.

Abstract

The present invention relates to the field of pharmaceutical application, and particularly to the treatment of pancreatic cancer with chiauranib. The present invention provides use of chiauranib or a derivative thereof in preparing a medicament for preventing and/or ameliorating and/or treating pancreatic cancer. Also disclosed is use of chiauranib or a derivative thereof in combination with an HDAC inhibitor or in combination with an FAK inhibitor in preparing a medicament for preventing and/or ameliorating and/or treating pancreatic cancer. According to the present invention, the chiauranib monotherapy, combined use with the HDAC inhibitor, or combined use with the FAK inhibitor can effectively prevent and/or ameliorate and/or treat pancreatic cancer.

Description

西奥罗尼在抗胰腺癌中的用途The use of Siorani in the fight against pancreatic cancer 技术领域Technical field
本发明涉及药物应用领域，尤其涉及西奥罗尼在制备治疗胰腺癌的药物中的新用途。The present invention relates to the field of pharmaceutical applications, and in particular to the new use of Siorani in the preparation of medicines for treating pancreatic cancer.
背景技术Background technique
胰腺癌是发生于胰腺外分泌腺的恶性肿瘤。胰腺恶性肿瘤可来自胰腺外分泌腺、内分泌腺或非上皮组织，其中95％为胰腺癌，该疾病预后最差，其发病率和死亡率很高。主要是使用药物、手术、放化疗等方法治疗疾病。胰腺癌的治疗仍以争取手术切除为主，对不能手术者常做姑息性短路手术、化学疗法和放射治疗。目前尚无有效的单个化疗药物或联合的化疗方案，可延长胰腺癌患者的生命或改善生活质量。常用化疗药物有吉西他滨、5-氟尿嘧啶、顺铂、泰素帝、草酸铂、阿瓦斯汀、卡培他滨等。Pancreatic cancer is a malignant tumor that occurs in the exocrine pancreatic gland. Pancreatic malignant tumors can originate from pancreatic exocrine glands, endocrine glands or non-epithelial tissues, 95% of which are pancreatic cancer. This disease has the worst prognosis and has high morbidity and mortality. It mainly uses drugs, surgery, radiotherapy and chemotherapy to treat diseases. The main treatment for pancreatic cancer is surgical resection, and palliative short-circuit surgery, chemotherapy and radiotherapy are often used for those who are inoperable. Currently, there is no effective single chemotherapy drug or combination chemotherapy regimen that can prolong the life or improve the quality of life of patients with pancreatic cancer. Commonly used chemotherapy drugs include gemcitabine, 5-fluorouracil, cisplatin, Taxotere, platinum oxalate, Avastin, capecitabine, etc.
西奥罗尼是深圳微芯生物科技股份有限公司自主研发的具有完全知识产权的全新蛋白激酶抑制剂。西奥罗尼是以多蛋白激酶为靶点的小分子抗肿瘤靶向药物，通过对VEGFR/PDGFR/c-Kit、Aurora B、CSF-1R靶点的高选择抑制活性，具有抗肿瘤血管生成、抑制肿瘤细胞有丝分裂、调控肿瘤炎性微环境等三通路抗肿瘤协同作用机制，发挥综合抗肿瘤作用。与传统的VEGFR类靶向抑制剂(如舒尼替尼/Sunitinib、索拉菲尼/Sorafenib等)相比，西奥罗尼对有丝分裂关键酶Aurora B的抑制活性是其所特有的，具有潜在的降低肿瘤组织基因组不稳定性及抑制肿瘤细胞转移的作用。西奥罗尼通过抑制肿瘤血管生成、细胞有丝分裂和肿瘤炎性微环境三种互补的作用机制发挥抗肿瘤活性，同时其高靶标选择性也降低了因脱靶效应带来的副作用风险。Ciaroni is a new protein kinase inhibitor with complete intellectual property rights independently developed by Shenzhen Microchip Biotechnology Co., Ltd. Scioronib is a small molecule anti-tumor targeted drug targeting multiple protein kinases. It has anti-tumor angiogenesis through its high selective inhibitory activity on VEGFR/PDGFR/c-Kit, Aurora B, and CSF-1R targets. It exerts a comprehensive anti-tumor effect through a three-pathway anti-tumor synergistic mechanism, including inhibiting tumor cell mitosis and regulating the tumor inflammatory microenvironment. Compared with traditional VEGFR targeted inhibitors (such as sunitinib/Sunitinib, sorafenib/Sorafenib, etc.), Cioranib's inhibitory activity on the key mitotic enzyme Aurora B is unique and has potential It can reduce the genomic instability of tumor tissue and inhibit the metastasis of tumor cells. Scioronib exerts anti-tumor activity through three complementary mechanisms of inhibiting tumor angiogenesis, cell mitosis and tumor inflammatory microenvironment. At the same time, its high target selectivity also reduces the risk of side effects caused by off-target effects.
CN200910223861.5公开了西奥罗尼化合物，其具体公开了一种萘酰胺的衍生物、其制备方法及应用。该类化合物同时具有蛋白激酶抑制活性和组蛋白去乙酰化酶抑制活性，可以用于治疗与蛋白激酶活性异常或组蛋白去乙酰化酶活性异常相关的疾病，包括炎症、自身免疫性疾病、癌症、神经系统疾病和神经退化性疾病、心血管疾病、代谢病、过敏、哮喘以及与激素相关的疾病。CN200910223861.5 discloses Sioroni compounds, which specifically discloses a naphthylamide derivative, its preparation method and application. This type of compound has both protein kinase inhibitory activity and histone deacetylase inhibitory activity, and can be used to treat diseases related to abnormal protein kinase activity or abnormal histone deacetylase activity, including inflammation, autoimmune diseases, and cancer. , neurological and neurodegenerative diseases, cardiovascular diseases, metabolic diseases, allergies, asthma and hormone-related diseases.
CN201610856945.2公开了西奥罗尼的非溶剂化晶体A、B、C及其制备方法，还涉及含有所述晶体的药物组合物，以及所述晶体在制备用于治疗与蛋白激 酶活性异常或组蛋白去乙酰化酶活性异常相关的疾病的药物中的应用。CN201610856945.2 discloses unsolvated crystals A, B, and C of cealoni and their preparation methods. It also relates to pharmaceutical compositions containing the crystals, and the preparation of the crystals for the treatment of protein steroid hormones. Application in drugs for diseases related to abnormal enzyme activity or abnormal histone deacetylase activity.
目前尚未有关于西奥罗尼单用或联用于治疗胰腺癌的研究和报道。There are currently no studies or reports on the use of ceopronib alone or in combination with pancreatic cancer.
发明内容Contents of the invention
本发明的目的是提供西奥罗尼或其衍生物在制备用于预防和/或改善和/或治疗胰腺癌的药物中的用途。The object of the present invention is to provide the use of cealoni or its derivatives in the preparation of medicaments for preventing and/or improving and/or treating pancreatic cancer.
上述用途中，所述西奥罗尼衍生物包括其可药用盐、非溶剂化晶体A、B或C。西奥罗尼的非溶剂化晶体A、B和C公开于CN201610856945.2中，其全文内容被引入本发明。In the above-mentioned uses, the cioronil derivatives include pharmaceutically acceptable salts, unsolvated crystals A, B or C thereof. Unsolvated crystals A, B and C of Sioronil are disclosed in CN201610856945.2, the entire content of which is incorporated into the present invention.
上述用途中，所述西奥罗尼或其衍生物单位剂量为5-100mg。优选为10-100mg。更优选为25mg。In the above-mentioned uses, the unit dosage of ceoranib or its derivatives is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
本发明还提供了西奥罗尼或其衍生物联合HDAC抑制剂在制备用于预防和/或改善和/或治疗胰腺癌的药物中的用途。The present invention also provides the use of cearoni or its derivatives in combination with an HDAC inhibitor in the preparation of medicaments for preventing and/or improving and/or treating pancreatic cancer.
上述用途中，所述西奥罗尼衍生物包括其可药用盐、非溶剂化晶体A、B或C。西奥罗尼的非溶剂化晶体A、B和C公开于CN201610856945.2中，其全文内容被引入本发明。In the above-mentioned uses, the cioronil derivatives include pharmaceutically acceptable salts, unsolvated crystals A, B or C thereof. Unsolvated crystals A, B and C of Sioronil are disclosed in CN201610856945.2, the entire content of which is incorporated into the present invention.
上述用途中，所述HDAC抑制剂选自恩替诺特(Entinostat)、伏立诺他(Vorinostat)、帕比司他(Panobinostat)、莫西司他(Mocetinostat)、贝利司他(Belinostat)、普雷司他(Pracinostat)、罗米地辛(Romidepsin)、西达本胺(Chidamide)，或其衍生物。In the above uses, the HDAC inhibitor is selected from the group consisting of Entinostat, Vorinostat, Panobinostat, Mocetinostat, and Belinostat. , Pracinostat, Romidepsin, Chidamide, or derivatives thereof.
优选的，所述HDAC抑制剂选自西达本胺或其衍生物。Preferably, the HDAC inhibitor is selected from chidamide or its derivatives.
上述用途中，所述西达本胺衍生物包括其可药用盐、对映异构体、晶型A或晶型B。CN201210489178.8公开了西达本胺的晶型A和晶型B，CN201410136761.X公开了西达本胺的对映异构体，它们被全文引入本发明中。In the above uses, the chidamide derivative includes its pharmaceutically acceptable salt, enantiomer, crystal form A or crystal form B. CN201210489178.8 discloses the crystalline form A and crystalline form B of chidamide, and CN201410136761.X discloses the enantiomers of chidamide, which are fully incorporated into the present invention.
上述用途中，所述西奥罗尼或其衍生物的单位剂量为5-100mg。优选为10-100mg。更优选为25mg。In the above-mentioned uses, the unit dosage of ceoranib or its derivatives is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
上述用途中，所述西达本胺或其衍生物的单位剂量为5-100mg。优选为5-60mg。更优选为5mg。In the above uses, the unit dose of chidamide or its derivative is 5-100 mg. Preferably it is 5-60 mg. More preferably, it is 5 mg.
本发明还提供了西奥罗尼或其衍生物联合FAK抑制剂在制备用于预防和/或改善和/或治疗胰腺癌的药物中的用途。 The present invention also provides the use of cealoni or its derivatives in combination with FAK inhibitors in the preparation of medicaments for preventing and/or improving and/or treating pancreatic cancer.
上述用途中，所述西奥罗尼衍生物包括其可药用盐、非溶剂化晶体A、B或C。西奥罗尼的非溶剂化晶体A、B和C公开于CN201610856945.2中，其全文内容被引入本发明。In the above-mentioned uses, the cioronil derivatives include pharmaceutically acceptable salts, unsolvated crystals A, B or C thereof. Unsolvated crystals A, B and C of Sioronil are disclosed in CN201610856945.2, the entire content of which is incorporated into the present invention.
上述用途中，所述FAK抑制剂选自PND1186、GSK-2256098、TAE226、PF-562271、PF-431396、PF-04554878、BI-4464。优选的，所述FAK抑制剂选自PND1186。In the above uses, the FAK inhibitor is selected from PND1186, GSK-2256098, TAE226, PF-562271, PF-431396, PF-04554878, and BI-4464. Preferably, the FAK inhibitor is selected from PND1186.
上述用途中，所述西奥罗尼或其衍生物的单位剂量为5-100mg。优选为10-100mg。更优选为25mg。In the above-mentioned uses, the unit dosage of ceoranib or its derivatives is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
上述用途中，所述PND1186的单位剂量为10-200mg。优选为20-200mg。更优选为200mg。In the above uses, the unit dose of PND1186 is 10-200 mg. Preferably it is 20-200 mg. More preferably, it is 200 mg.
本发明还提供了西奥罗尼或其衍生物用于预防和/或改善和/或治疗胰腺癌。The present invention also provides cealoni or its derivatives for preventing and/or improving and/or treating pancreatic cancer.
上述用途中，所述西奥罗尼衍生物包括其可药用盐、非溶剂化晶体A、B或C。西奥罗尼的非溶剂化晶体A、B和C公开于CN201610856945.2中，其全文内容被引入本发明。In the above-mentioned uses, the cioronil derivatives include pharmaceutically acceptable salts, unsolvated crystals A, B or C thereof. Unsolvated crystals A, B and C of Sioronil are disclosed in CN201610856945.2, the entire content of which is incorporated into the present invention.
上述用途中，所述西奥罗尼或其衍生物单位剂量为5-100mg。优选为10-100mg。更优选为25mg。In the above-mentioned uses, the unit dosage of ceoranib or its derivatives is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
本发明还提供了西奥罗尼或其衍生物联合HDAC抑制剂用于预防和/或改善和/或治疗胰腺癌。The present invention also provides ceopronil or its derivatives combined with HDAC inhibitors for preventing and/or improving and/or treating pancreatic cancer.
上述用途中，所述西奥罗尼衍生物包括其可药用盐、非溶剂化晶体A、B或C。西奥罗尼的非溶剂化晶体A、B和C公开于CN201610856945.2中，其全文内容被引入本发明。In the above-mentioned uses, the cioronil derivatives include pharmaceutically acceptable salts, unsolvated crystals A, B or C thereof. Unsolvated crystals A, B and C of Sioronil are disclosed in CN201610856945.2, the entire content of which is incorporated into the present invention.
上述用途中，所述HDAC抑制剂选自恩替诺特(Entinostat)、伏立诺他(Vorinostat)、帕比司他(Panobinostat)、莫西司他(Mocetinostat)、贝利司他(Belinostat)、普雷司他(Pracinostat)、罗米地辛(Romidepsin)、西达本胺(Chidamide)，或其衍生物。In the above uses, the HDAC inhibitor is selected from the group consisting of Entinostat, Vorinostat, Panobinostat, Mocetinostat, and Belinostat. , Pracinostat, Romidepsin, Chidamide, or derivatives thereof.
优选的，所述HDAC抑制剂选自西达本胺或其衍生物。Preferably, the HDAC inhibitor is selected from chidamide or its derivatives.
上述用途中，所述西达本胺衍生物包括其可药用盐、对映异构体、晶型A或晶型B。CN201210489178.8公开了西达本胺的晶型A和晶型B，CN201410136761.X公开了西达本胺的对映异构体，它们被全文引入本发明中。 In the above uses, the chidamide derivative includes its pharmaceutically acceptable salt, enantiomer, crystal form A or crystal form B. CN201210489178.8 discloses the crystalline form A and crystalline form B of chidamide, and CN201410136761.X discloses the enantiomers of chidamide, which are fully incorporated into the present invention.
上述用途中，所述西奥罗尼或其衍生物的单位剂量为5-100mg。优选为10-100mg。更优选为25mg。In the above-mentioned uses, the unit dosage of ceoranib or its derivatives is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
上述用途中，所述西达本胺或其衍生物的单位剂量为5-100mg。优选为5-60mg。更优选为5mg。In the above uses, the unit dose of chidamide or its derivative is 5-100 mg. Preferably it is 5-60 mg. More preferably, it is 5 mg.
本发明还提供了西奥罗尼或其衍生物联合FAK抑制剂用于预防和/或改善和/或治疗胰腺癌。The present invention also provides ceoronil or a derivative thereof combined with a FAK inhibitor for preventing and/or improving and/or treating pancreatic cancer.
上述用途中，所述西奥罗尼衍生物包括其可药用盐、非溶剂化晶体A、B或C。西奥罗尼的非溶剂化晶体A、B和C公开于CN201610856945.2中，其全文内容被引入本发明。In the above-mentioned uses, the cioronil derivatives include pharmaceutically acceptable salts, unsolvated crystals A, B or C thereof. Unsolvated crystals A, B and C of Sioronil are disclosed in CN201610856945.2, the entire content of which is incorporated into the present invention.
上述用途中，所述FAK抑制剂选自PND1186、GSK-2256098、TAE226、PF-562271、PF-431396、PF-04554878、BI-4464。优选的，所述FAK抑制剂选自PND1186。In the above uses, the FAK inhibitor is selected from PND1186, GSK-2256098, TAE226, PF-562271, PF-431396, PF-04554878, and BI-4464. Preferably, the FAK inhibitor is selected from PND1186.
上述用途中，所述西奥罗尼或其衍生物的单位剂量为5-100mg。优选为10-100mg。更优选为25mg。In the above-mentioned uses, the unit dosage of ceoranib or its derivatives is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
上述用途中，所述PND1186单位剂量为10-200mg。优选为20-200mg。更优选为200mg。In the above uses, the unit dose of PND1186 is 10-200 mg. Preferably it is 20-200 mg. More preferably, it is 200 mg.
本发明还提供了一种药物组合物，其包括作为活性成分的西奥罗尼或其衍生物和FAK抑制剂，以及药学上可接受的辅料。The present invention also provides a pharmaceutical composition, which includes cealanib or its derivatives and a FAK inhibitor as active ingredients, as well as pharmaceutically acceptable excipients.
上述药物组合物中，所述FAK抑制剂选自PND1186、GSK-2256098、TAE226、PF-562271、PF-431396、PF-04554878、BI-4464。优选的，所述FAK抑制剂为PND1186。In the above pharmaceutical composition, the FAK inhibitor is selected from PND1186, GSK-2256098, TAE226, PF-562271, PF-431396, PF-04554878, and BI-4464. Preferably, the FAK inhibitor is PND1186.
上述药物组合物中，所述西奥罗尼或其衍生物的单位剂量为5-100mg。优选为10-100mg。更优选为25mg。In the above-mentioned pharmaceutical composition, the unit dose of ceoranib or its derivative is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
上述药物组合物中，所述PND1186的单位剂量为10-200mg。优选为20-200mg。更优选为200mg。In the above pharmaceutical composition, the unit dose of PND1186 is 10-200 mg. Preferably it is 20-200mg. More preferably, it is 200 mg.
本发明还提供了一种药盒，其包括上述所述的药物组合物。The present invention also provides a pharmaceutical kit, which includes the above-mentioned pharmaceutical composition.
上述药盒中，所述西奥罗尼或其衍生物和FAK抑制剂为具有相同或不同规格的单位制剂，所述西奥罗尼或其衍生物和所述FAK抑制剂置于同一容器中、或者分别置于不同容器中。In the above kit, the ceopronib or its derivatives and the FAK inhibitor are unit preparations with the same or different specifications, and the ceopronib or its derivative and the FAK inhibitor are placed in the same container. , or placed in different containers.
本发明还提供了预防和/或改善和/或治疗胰腺癌的方法，向有需要的患者施 用西奥罗尼或其衍生物，或者联合施用西奥罗尼或其衍生物和HDAC抑制剂，或者联合施用西奥罗尼或其衍生物和FAK抑制剂。The present invention also provides methods for preventing and/or improving and/or treating pancreatic cancer by administering them to patients in need. Use ceopronib or its derivatives, or co-administer ceopronib or its derivatives and an HDAC inhibitor, or co-administer ceopronib or its derivatives and a FAK inhibitor.
上述方法中，所述西奥罗尼衍生物包括其可药用盐、非溶剂化晶体A、B或C。In the above method, the cioronil derivative includes its pharmaceutically acceptable salt, unsolvated crystal A, B or C.
上述方法中，所述HDAC抑制剂选自恩替诺特(Entinostat)、伏立诺他(Vorinostat)、帕比司他(Panobinostat)、莫西司他(Mocetinostat)、贝利司他(Belinostat)、普雷司他(Pracinostat)、罗米地辛(Romidepsin)、西达本胺(Chidamide)，或其衍生物。优选的，所述HDAC抑制剂选自西达本胺或其衍生物In the above method, the HDAC inhibitor is selected from the group consisting of Entinostat, Vorinostat, Panobinostat, Mocetinostat, and Belinostat. , Pracinostat, Romidepsin, Chidamide, or derivatives thereof. Preferably, the HDAC inhibitor is selected from chidamide or its derivatives
上述方法中，所述FAK抑制剂选自PND1186、GSK-2256098、TAE226、PF-562271、PF-431396、PF-04554878、BI-4464。优选的，所述FAK抑制剂为PND1186In the above method, the FAK inhibitor is selected from PND1186, GSK-2256098, TAE226, PF-562271, PF-431396, PF-04554878, and BI-4464. Preferably, the FAK inhibitor is PND1186
上述方法中，所述西奥罗尼或其衍生物的单位剂量为5-100mg。优选为10-100mg。更优选为25mg。In the above method, the unit dose of ceoranib or its derivative is 5-100 mg. Preferably it is 10-100 mg. More preferably, it is 25 mg.
上述方法中，所述西奥罗尼衍生物包括其可药用盐、非溶剂化晶体A、B或C。西奥罗尼的非溶剂化晶体A、B和C公开于CN201610856945.2中，其全文内容被引入本发明。In the above method, the cioronil derivative includes its pharmaceutically acceptable salt, unsolvated crystal A, B or C. Unsolvated crystals A, B and C of Sioronil are disclosed in CN201610856945.2, the entire content of which is incorporated into the present invention.
上述方法中，所述西达本胺或其衍生物的单位剂量为5-100mg。优选为5-60mg。更优选为5mg。In the above method, the unit dose of chidamide or its derivative is 5-100 mg. Preferably it is 5-60 mg. More preferably, it is 5 mg.
上述方法中，所述西达本胺衍生物包括其可药用盐、对映异构体、晶型A或晶型B。CN201210489178.8公开了西达本胺的晶型A和晶型B，CN201410136761.X公开了西达本胺的对映异构体，它们被全文引入本发明中。In the above method, the chidamide derivative includes its pharmaceutically acceptable salt, enantiomer, crystal form A or crystal form B. CN201210489178.8 discloses the crystalline form A and crystalline form B of chidamide, and CN201410136761.X discloses the enantiomers of chidamide, which are fully incorporated into the present invention.
上述方法中，所述PND1186的单位剂量为10-200mg。优选为20-200mg。更优选为200mg。In the above method, the unit dose of PND1186 is 10-200 mg. Preferably it is 20-200 mg. More preferably, it is 200 mg.
本发明西奥罗尼单药、西奥罗尼联用HDAC抑制剂以及西奥罗尼联用FAK抑制剂对治疗胰腺癌具有显著的作用，为胰腺癌的治疗提供了一种更好的选择。The invention has significant effects on the treatment of pancreatic cancer, including ceopronib alone, ceopronib combined with an HDAC inhibitor, and ceopronib combined with a FAK inhibitor, and provides a better choice for the treatment of pancreatic cancer. .
附图说明Description of the drawings
图1实施例1中不同组别胰腺癌PDX模型小鼠的肿瘤体积变化；Figure 1: Tumor volume changes of different groups of pancreatic cancer PDX model mice in Example 1;
图2实施例1中B00329PDX模型小鼠的终点解剖肿瘤大小； Figure 2 Endpoint anatomical tumor size of B00329PDX model mice in Example 1;
图3实施例1中不同组别胰腺癌PDX模型小鼠的肿瘤重量变化；G1：Vehicle组；G2：西奥罗尼组；注：采用独立样本T检验，vs G1*：P<0.05,**：P<0.01,***：P<0.001；Figure 3 Changes in tumor weight of different groups of pancreatic cancer PDX model mice in Example 1; G1: Vehicle group; G2: Sioroni group; Note: Independent sample T test is used, vs G1*: P<0.05,* *: P<0.01,***: P<0.001;
图4实施例1中不同组别胰腺癌PDX模型小鼠的体重变化；Figure 4 Body weight changes of different groups of pancreatic cancer PDX model mice in Example 1;
图5实施例2中不同组别胰腺癌PDX模型小鼠的肿瘤体积变化；Figure 5: Tumor volume changes in different groups of pancreatic cancer PDX model mice in Example 2;
图6实施例2中不同组别胰腺癌PDX模型小鼠的终点肿瘤照片；Figure 6: End-point tumor photos of different groups of pancreatic cancer PDX model mice in Example 2;
图7实施例2中不同组别胰腺癌PDX模型小鼠的肿瘤重量变化；G3：Vehicle组；G4：西奥罗尼组；注：采用独立样本T检验，vs G3*：P<0.05,**：P<0.01,***：P<0.001；Figure 7 Changes in tumor weight of different groups of pancreatic cancer PDX model mice in Example 2; G3: Vehicle group; G4: Sciorone group; Note: Independent sample T test is used, vs G3*: P<0.05,* *: P<0.01,***: P<0.001;
图8实施例2中不同组别胰腺癌PDX模型小鼠的体重变化；Figure 8 Body weight changes of different groups of pancreatic cancer PDX model mice in Example 2;
图9实施例3中不同组别小鼠原位胰腺接种mPAKPC胰腺癌模型的肿瘤重量变化；G1：Vehicle组；G2：西奥罗尼组；G3：PND1186组；G4：西奥罗尼+PND1186联用组；注：采用独立样本T检验，vs G1*：P<0.05,**：P<0.01,***：P<0.001；Figure 9 Changes in tumor weight of mPA KPC pancreatic cancer model in different groups of mice in situ pancreatic inoculation in Example 3; G1: Vehicle group; G2: Ciopronib group; G3: PND1186 group; G4: Ciopronib+ PND1186 combination group; Note: Independent sample T test is used, vs G1*: P<0.05, **: P<0.01, ***: P<0.001;
图10实施例3中不同组别小鼠原位胰腺接种mPAKPC胰腺癌模型的体重变化；Figure 10 Body weight changes of mPA KPC pancreatic cancer model of orthotopic pancreatic inoculation of different groups of mice in Example 3;
图11实施例4中不同组别小鼠原位胰腺接种mPAKPC-luciferase胰腺癌模型的荧光成像照片；Figure 11 Fluorescence imaging photos of mPA KPC -luciferase pancreatic cancer model in situ pancreatic inoculation of different groups of mice in Example 4;
图12实施例4中不同组别小鼠原位胰腺接种mPAKPC-luciferase胰腺癌模型的肿瘤体积变化(荧光强度)；Figure 12: Tumor volume changes (fluorescence intensity) in the mPA KPC -luciferase pancreatic cancer model of orthotopic pancreatic inoculation of different groups of mice in Example 4;
图13实施例4中不同组别小鼠原位胰腺接种mPAKPC-luciferase胰腺癌模型的体重变化。Figure 13: Body weight changes in the mPA KPC -luciferase pancreatic cancer model of orthotopic pancreatic inoculation of different groups of mice in Example 4.
具体实施方式Detailed ways
本发明公开了西奥罗尼对胰腺癌的治疗用途，本领域技术人员可以借鉴本文内容，适当改进实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明所述应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述应用进行改动或适当变更与组合，来实现和应用本发明技术。The present invention discloses the therapeutic use of Sioronil for pancreatic cancer. Persons skilled in the art can learn from the content of this article and make appropriate improvements and implementations. It should be noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are deemed to be included in the present invention. The applications described in the present invention have been described through preferred embodiments. Relevant personnel can obviously make changes or appropriate changes and combinations to the applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention. .
实施例1西奥罗尼单药在NCG小鼠胰腺癌PDX模型(B00329)的药效学探索 Example 1 Exploration of the Pharmacodynamics of Sioronib Single Agent in NCG Mouse Pancreatic Cancer PDX Model (B00329)
1.实验方法1. Experimental methods
胰腺癌PDX模型编号B00329为胰尾部位，PDX模型来源于集萃药康生物有限公司。将PDX瘤块复苏后以2.5mm×2.5mm×2.5mm接种到36只NCG雌性小鼠中(集萃药康生物有限公司)，每周进行肿瘤体积的测量(肿瘤体积(mm3)＝0.5×肿瘤长径×肿瘤短径2)，待肿瘤体积于100mm3左右挑选20只肿瘤体积接近的动物进行分组，其中Vehicle(G1)和西奥罗尼组(G2)各10只。将分组当天定义为第0天(D0)，从D0开始给药，给药剂量如表1所示。The pancreatic cancer PDX model number B00329 is the tail of the pancreas, and the PDX model is from Jicui Yaokang Biological Co., Ltd. After resuscitation, the PDX tumor mass was inoculated into 36 NCG female mice (Jicui Yaokang Biological Co., Ltd.) at 2.5 mm × 2.5 mm × 2.5 mm, and the tumor volume was measured every week (tumor volume (mm 3 ) = 0.5 × Tumor long diameter × tumor short diameter 2 ), when the tumor volume is around 100 mm 3 , 20 animals with similar tumor volumes are selected and divided into groups, including 10 animals each in Vehicle (G1) and Sciorone group (G2). The day of grouping was defined as day 0 (D0), and administration started from D0. The dosage is shown in Table 1.
表1各组给药剂量与方法
Table 1 Dosage and method of administration in each group
注：给药体积按照小鼠体重调整，10μL/g×小鼠体重(g)。Note: The dosage volume is adjusted according to the mouse body weight, 10 μL/g × mouse body weight (g).
药物配制：Drug Preparation:
Vehicle组(模型组)：0.5％CMC+0.1％Tween80；Vehicle group (model group): 0.5% CMC+0.1% Tween80;
西奥罗尼组：相应质量的西奥罗尼加入到与Vehicle组相同的溶剂中，涡旋震荡成浓度为1mg/mL混悬液。Scioronil group: The corresponding mass of Xioronil was added to the same solvent as the Vehicle group, and vortexed to form a suspension with a concentration of 1 mg/mL.
各组于D3、D7、D10、D14、D17、D21称量小鼠体重，测量肿瘤体积，计算TGITV，计算公式如下：
The mice in each group were weighed on D3, D7, D10, D14, D17, and D21, the tumor volume was measured, and TGI TV was calculated. The calculation formula is as follows:
Vnt：编号为n的小鼠在第t天的肿瘤体积V nt : Tumor volume of mouse numbered n on day t
Vn0：编号为n的小鼠在第0天的肿瘤体积V n0 : Tumor volume of mouse number n on day 0
RTVn：编号为n的小鼠在第t天的肿瘤相对体积RTV n : relative tumor volume of mouse numbered n on day t
mean RTVtreat：给药组RTV平均值mean RTV treat : mean RTV of the dosing group
mean RTVvehicle：Vehicle组RTV平均值mean RTV vehicle : Vehicle group RTV average
实验终点为D21，剥离整个胰腺拍照、称重，取肿瘤样品固定，计算TGITW(肿瘤重量抑制率)，计算公式如下：
TGITW＝(1-meanTW treat/meanTW vehicle)x100％The end point of the experiment is D21. The entire pancreas is peeled off, photographed, weighed, and tumor samples are taken and fixed. The TGI TW (tumor weight inhibition rate) is calculated. The calculation formula is as follows:
TGI TW = (1-meanTW treat/meanTW vehicle)x100%
meanTWtreat：给药组小鼠终点处理时肿瘤重量的平均值 meanTWtreat: the average tumor weight of mice in the drug group at the end of treatment
meanTW vehicle：Vehicle组小鼠终点处理时肿瘤重量的平均值meanTW vehicle: the average tumor weight of mice in the Vehicle group at the end of treatment
实验结果以平均值±标准误差(Mean±SEM)表示。两组样本之间比较采用独立样本T检验(T-Test)，数据使用SPSS进行分析，P<0.05为具有显著性差异。作图软件为Graphpad prism。Experimental results are expressed as mean±standard error (Mean±SEM). The independent sample T test (T-Test) was used to compare the two groups of samples, and the data was analyzed using SPSS. P<0.05 was considered a significant difference. The drawing software is Graphpad prism.
2.实验结果2.Experimental results
2.1西奥罗尼显著抑制PDX肿瘤生长2.1 Sioronil significantly inhibits PDX tumor growth
如图1所示，该PDX模型肿瘤体积随着时间在递增，而西奥罗尼给药组肿瘤生长速度显著低于对照组。如表2所示，在D10、D14、D17、D21时，与对照组(vehicle)相比，西奥罗尼组的肿瘤体积明显减小，D10时具有显著性差异(P<0.05)，D14时具有显著性差异(P<0.01)，D17、D21时具有极显著性差异(P<0.001)。以上数据说明西奥罗尼可以显著抑制PDX肿瘤的生长。As shown in Figure 1, the tumor volume of the PDX model increased over time, and the tumor growth rate in the Cioranib administration group was significantly lower than that in the control group. As shown in Table 2, on D10, D14, D17, and D21, compared with the control group (vehicle), the tumor volume of the Cioranib group was significantly reduced, with a significant difference on D10 (P<0.05), and on D14 There was a significant difference on D17 and D21 (P<0.01), and there was a highly significant difference on D17 and D21 (P<0.001). The above data demonstrate that Sioronib can significantly inhibit the growth of PDX tumors.
表2不同组别肿瘤体积抑制率变化(TGITV)和肿瘤体积p值统计分析
Table 2 Statistical analysis of changes in tumor volume inhibition rate (TGI TV ) and tumor volume p-value in different groups
注：采用独立样本T检验，vs G1*：P<0.05,**：P<0.01,***：P<0.001。Note: Using independent sample T test, vs G1*: P<0.05, **: P<0.01, ***: P<0.001.
2.2西奥罗尼终点显著降低肿瘤重量2.2 Sioroni endpoint significantly reduces tumor weight
如图2所示，终点解剖后对照组肿瘤大小比较均匀，重量约为0.31g，西奥罗尼给药21天后显著降低肿瘤重量，均值约为0.13g(图3)。可以看出，西奥罗尼给药组可以显著降低肿瘤重量(p＝0.000016)。终点的TGITW为57.58％。As shown in Figure 2, after end-point anatomy, the tumor size in the control group was relatively uniform, with a weight of approximately 0.31g. Cioranib significantly reduced the tumor weight after 21 days of administration, with an average value of approximately 0.13g (Figure 3). It can be seen that the Sioronil administration group can significantly reduce tumor weight (p=0.000016). The TGI TW of the end point was 57.58%.
2.3西奥罗尼不降低动物体重2.3 Sioroni does not reduce animal weight
如图4所示，整个给药期间，对照组和给药组动物体重都没有显著变化，说明该剂量下动物对西奥罗尼耐受。As shown in Figure 4, during the entire administration period, there was no significant change in the body weight of the animals in the control group and the administration group, indicating that the animals were tolerant to Cioranib at this dose.
3.实验结论3.Experimental conclusion
西奥罗尼单药能显著抑制PDX模型肿瘤生长和降低肿瘤重量，且对动物体重没有显著的影响。Scioronib alone can significantly inhibit tumor growth and reduce tumor weight in the PDX model, without significant impact on animal body weight.
实施例2西奥罗尼单药在NCG小鼠胰腺癌PDX模型(B00455)的药效学探Example 2 Study on the pharmacodynamics of Cioronib single drug in NCG mouse pancreatic cancer PDX model (B00455)
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1.实验方法1. Experimental methods
胰腺癌PDX模型编号B00455为胰尾部位，PDX模型来源于集萃药康生物有限公司。将PDX瘤块复苏后以2.5mm×2.5mm×2.5mm大小接种到36只NCG雌性小鼠中(集萃药康生物有限公司)，每周进行肿瘤体积的测量(肿瘤体积(mm3) ＝0.5×肿瘤长径×肿瘤短径2)，待肿瘤体积于100mm3左右挑选20只肿瘤体积接近的动物进行分组，其中Vehicle(G3)和西奥罗尼组(G4)各10只。将分组当天定义为第0天(D0)，从D0开始给药，给药剂量如表3所示。The pancreatic cancer PDX model number B00455 is the tail of the pancreas, and the PDX model is from Jicui Yaokang Biological Co., Ltd. After resuscitation, the PDX tumor mass was inoculated into 36 NCG female mice (Jicui Yaokang Biological Co., Ltd.) with a size of 2.5 mm × 2.5 mm × 2.5 mm, and the tumor volume was measured every week (tumor volume (mm 3 ) =0.5×tumor long diameter×tumor short diameter 2 ), when the tumor volume is around 100 mm 3 , 20 animals with similar tumor volumes are selected and divided into groups, including 10 animals each in Vehicle (G3) and Sciorone group (G4). The day of grouping was defined as day 0 (D0), and administration started from D0. The dosage is shown in Table 3.
表3各组给药剂量与方法
Table 3 Dosage and method of administration in each group
药物配制：Drug Preparation:
Vehicle组(模型组)：0.5％CMC+0.1％Tween80；Vehicle group (model group): 0.5% CMC+0.1% Tween80;
西奥罗尼组：相应质量的西奥罗尼加入到与Vehicle组相同的溶剂中，涡旋震荡成浓度为1mg/mL混悬液。Scioronil group: The corresponding mass of Xioronil was added to the same solvent as the Vehicle group, and vortexed to form a suspension with a concentration of 1 mg/mL.
给药后，各组于D2、D5、D7、D12、D16、D19、D22称量小鼠体重，测量肿瘤体积，计算TGITV(肿瘤体积抑制率)，实验终点为D22。After administration, mice in each group were weighed on D2, D5, D7, D12, D16, D19, and D22, tumor volume was measured, and TGI TV (tumor volume inhibition rate) was calculated. The experimental end point was D22.
TGITV，计算公式如下：
TGI TV , the calculation formula is as follows:
Vnt：编号为n的小鼠在第t天的肿瘤体积V nt : Tumor volume of mouse numbered n on day t
Vn0：编号为n的小鼠在第0天的肿瘤体积V n0 : Tumor volume of mouse number n on day 0
RTVn：编号为n的小鼠在第t天的肿瘤相对体积RTV n : relative tumor volume of mouse numbered n on day t
mean RTVtreat：给药组RTV平均值mean RTV treat : mean RTV of the dosing group
mean RTVvehicle：Vehicle组RTV平均值mean RTV vehicle : Vehicle group RTV average
实验结果以平均值±标准误差(Mean±SEM)表示。两组样本之间比较采用独立样本T检验(T-Test)，数据使用SPSS进行分析，P<0.05为具有显著性差异。作图软件为Graphpad prism。Experimental results are expressed as mean±standard error (Mean±SEM). The independent sample T test (T-Test) was used to compare the two groups of samples, and the data was analyzed using SPSS. P<0.05 was considered a significant difference. The drawing software is Graphpad prism.
2.实验结果2.Experimental results
2.1西奥罗尼显著抑制PDX肿瘤生长2.1 Sioronil significantly inhibits PDX tumor growth
如图5所示，该PDX模型肿瘤体积随着时间在递增，而西奥罗尼给药组肿瘤生长速度显著低于对照组。如表4所示，在D12、D16、D19、D22时，与Vehicle组(G3)相比，西奥罗尼组(G4)的肿瘤体积明显减小，D12时具有显著性差异(P<0.01)，D16、D19、D22时具有极显著性差异(P<0.001)。提示西奥罗尼可 以显著抑制肿瘤生长。As shown in Figure 5, the tumor volume of the PDX model increased over time, and the tumor growth rate in the Cioranib administration group was significantly lower than that in the control group. As shown in Table 4, on D12, D16, D19, and D22, compared with the Vehicle group (G3), the tumor volume of the Ciorani group (G4) was significantly reduced, and there was a significant difference on D12 (P<0.01 ), with extremely significant differences on D16, D19 and D22 (P<0.001). Tips from Siolo Nico to significantly inhibit tumor growth.
表4不同组别肿瘤体积抑制率变化(TGITV)和肿瘤体积p值统计分析
Table 4 Statistical analysis of changes in tumor volume inhibition rate (TGI TV ) and tumor volume p value in different groups
注：采用独立样本T检验，vs G3*：P<0.05,**：P<0.01,***：P<0.001。Note: Using independent sample T test, vs G3*: P<0.05, **: P<0.01, ***: P<0.001.
2.2西奥罗尼终点显著降低肿瘤重量2.2 Sioroni endpoint significantly reduces tumor weight
如图6所示，终点解剖后对照组肿瘤大小比较均匀，重量约为0.83g，西奥罗尼给药21天后显著降低肿瘤重量，均值约为0.38g(图7)。可以看出，西奥罗尼给药组可以显著降低肿瘤重量(p＝1.2914E-7)。终点的TGITW为54.20％。As shown in Figure 6, after end-point anatomy, the tumor size in the control group was relatively uniform, with a weight of approximately 0.83g. Cioranib significantly reduced the tumor weight after 21 days of administration, with an average value of approximately 0.38g (Figure 7). It can be seen that the Sioronil administration group can significantly reduce tumor weight (p=1.2914E-7). The TGI TW of the end point was 54.20%.
2.3西奥罗尼不降低动物体重2.3 Sioroni does not reduce animal weight
如图8所示，整个给药期间，对照组和给药组动物体重都没有显著变化，说明该剂量下动物对西奥罗尼耐受。As shown in Figure 8, during the entire administration period, there was no significant change in the body weight of the animals in the control group and the administration group, indicating that the animals were tolerant to Sioronil at this dose.
3.实验结论3.Experimental conclusion
西奥罗尼单药能显著抑制PDX模型肿瘤生长和降低肿瘤重量，且对动物体重没有显著的影响。Scioronib alone can significantly inhibit tumor growth and reduce tumor weight in the PDX model, without significant impact on animal body weight.
实施例3在C57BL/6小鼠胰腺癌mPAKPC原位移植模型中的药效学评价Example 3 Pharmacodynamic evaluation in the mPA KPC orthotopic transplantation model of pancreatic cancer in C57BL/6 mice
1.实验方法1. Experimental methods
mPAKPC原位自发胰腺癌模型是将小鼠的KRAS(G12D)和TP53进行突变后形成的肿瘤模型，将瘤块分离并重新原位移植到小鼠胰腺，形成肿瘤模型并用于药效研究。动物来源：集萃药康生物有限公司。The mPA KPC orthotopic spontaneous pancreatic cancer model is a tumor model formed by mutating KRAS (G12D) and TP53 in mice. The tumor mass is isolated and re-transplanted orthotopically into the mouse pancreas to form a tumor model and used for drug efficacy research. Animal source: Jicui Yaokang Biological Co., Ltd.
40只5～6周龄的C57BL/6雌性小鼠原位胰腺接种mPAKPC瘤块(集萃药康生物有限公司)，接种瘤块大小为2mm*2mm*2mm/只。于接种后第6天进行分组，G1Vehicle组，G2西奥罗尼组，G3PND1186组(PND1186购自上海楼岚生物科技有限公司)，G4西奥罗尼+PND1186联用组，并将分组当天定义为第0天(D0)。从D0开始给药，给药剂量如表5所示。Forty C57BL/6 female mice aged 5 to 6 weeks were inoculated into the pancreas in situ with mPA KPC tumor blocks (Jicui Yaokang Biological Co., Ltd.). The size of the inoculated tumor blocks was 2mm*2mm*2mm/mouse. Grouping will be carried out on the 6th day after vaccination, G1 Vehicle group, G2 Scioronib group, G3PND1186 group (PND1186 was purchased from Shanghai Loulan Biotechnology Co., Ltd.), G4 Scioronib + PND1186 combination group, and the groups will be defined on the day is day 0 (D0). Administration was started from D0, and the dosage was shown in Table 5.
表5各组给药剂量与方法

Table 5 Dosage and method of administration in each group

药物配制：Drug Preparation:
Vehicle组(模型组)：0.5％CMC+0.1％Tween80；Vehicle group (model group): 0.5% CMC+0.1% Tween80;
西奥罗尼组：相应质量的西奥罗尼加入到与Vehicle组相同的溶剂中，涡旋震荡成浓度0.5mg/mL和1mg/mL两种混悬液；Scioronil group: The corresponding mass of Xioronil was added to the same solvent as the Vehicle group, and vortexed to form two suspensions with concentrations of 0.5 mg/mL and 1 mg/mL;
PND1186：相应质量的PND1186加入到与Vehicle组相同的溶剂中，涡旋震荡成浓度3mg/mL和6mg/mL两种混悬液。PND1186: Add the corresponding mass of PND1186 to the same solvent as the Vehicle group, and vortex to form two suspensions with concentrations of 3mg/mL and 6mg/mL.
给药后，于D3、D7、D10、D14、D20称量小鼠体重；D21为实验终点，剥离整个胰腺拍照、称重，取肿瘤样品固定，计算TGITW(肿瘤重量抑制率)。
TGITW＝(1-meanTW treat/meanTW vehicle)x100％After administration, the mice were weighed on D3, D7, D10, D14, and D20; D21 was the end point of the experiment. The entire pancreas was peeled off, photographed, weighed, and tumor samples were taken and fixed, and TGI TW (tumor weight inhibition rate) was calculated.
TGI TW = (1-meanTW treat/meanTW vehicle)x100%
meanTWtreat：给药组小鼠终点处理时肿瘤重量的平均值meanTWtreat: the average tumor weight of mice in the drug group at the end of treatment
meanTW vehicle：Vehicle组小鼠终点处理时肿瘤重量的平均值meanTW vehicle: the average tumor weight of mice in the Vehicle group at the end of treatment
实验结果以平均值±标准误差(Mean±SEM)表示。两组样本之间比较采用独立样本T检验(T-Test)，数据使用SPSS进行分析，P<0.05为具有显著性差异。作图软件为Graphpad prism。Experimental results are expressed as mean±standard error (Mean±SEM). The independent samples T test (T-Test) was used to compare the two groups of samples, and the data was analyzed using SPSS. P<0.05 was considered a significant difference. The drawing software is Graphpad prism.
2.实验结果2.Experimental results
2.1西奥罗尼单药或联合PND1186具有显著的肿瘤抑制效果2.1 Sioronib alone or in combination with PND1186 has significant tumor inhibitory effect
如表6和图9所示，与Vehicle组(G1)相比，西奥罗尼组(G2)、PND1186组(G3)和西奥罗尼+PND1186联用组(G4)的瘤重显著减轻，G3组具有显著性差异(P<0.01)，G2和G4组具有极显著性差异(P<0.001)。G4联用组的肿瘤抑制效果优于西奥罗尼和PND1186单药，提示联合用药具备更好的肿瘤抑制优势。As shown in Table 6 and Figure 9, compared with the Vehicle group (G1), the tumor weight of the Ciopronib group (G2), PND1186 group (G3) and Ciopronib + PND1186 combination group (G4) was significantly reduced. , the G3 group has a significant difference (P<0.01), and the G2 and G4 groups have a highly significant difference (P<0.001). The tumor suppressive effect of the G4 combination group was better than that of Cioranib and PND1186 alone, suggesting that the combination has better tumor suppressive advantages.
表6不同组别肿瘤抑制率(TGITW)变化及P值统计分析
Table 6 Statistical analysis of changes in tumor inhibition rate (TGI TW ) in different groups and P value
注：数据以Mean±SEM表示。采用独立样本T检验，vs G1*：P<0.05,**：P<0.01,Note: Data are expressed as Mean ± SEM. Using independent sample T test, vs G1*: P<0.05,**: P<0.01,
***：P<0.001。 ***: P<0.001.
2.2西奥罗尼单药或联合PND1186未显著影响动物体重2.2 Sioronib alone or combined with PND1186 did not significantly affect animal weight
整个给药期间，西奥罗尼和PND1186都有稍微降低动物体重趋势，但体重降低并不显著，联合给药组动物体重与单药组比没有显著降低，说明联合给药的毒副作用不比单药组更严重。During the entire administration period, both Sioronil and PND1186 tended to slightly reduce the animal body weight, but the weight reduction was not significant. The animal body weight in the combined administration group was not significantly lower than that of the single drug group, indicating that the toxic and side effects of combined administration were no greater than those of the single drug group. The drug group was more serious.
3.实验总结3. Experiment summary
西奥罗尼和FAK抑制剂PND1186单药能显著抑制小鼠原位胰腺癌的肿瘤生长，而联合给药具有比两个单药更优的肿瘤抑制效果，且对动物体重没有显著的影响。The single drug Ciaroni and the FAK inhibitor PND1186 can significantly inhibit the tumor growth of orthotopic pancreatic cancer in mice, while the combined administration has a better tumor inhibitory effect than the two single drugs, and has no significant impact on the animal body weight.
实施例4、在C57BL/6小鼠胰腺癌mPAKPC-luciferase原位移植模型中的药效学评价(西奥罗尼联合西达本胺)Example 4. Pharmacodynamic evaluation in the mPA KPC -luciferase orthotopic transplantation model of pancreatic cancer in C57BL/6 mice (ceoranib combined with chidamide)
1.实验方法1. Experimental methods
mPAKPC原位自发胰腺癌模型是将小鼠的KRAS(G12D)和TP53进行突变后形成的肿瘤模型。将分离的肿瘤组织进行单细胞培养并在体外形成细胞系，该细胞系通过绿色荧光酶素(luciferase)标记，并混合基质胶原位移植到小鼠胰腺组织，形成原位肿瘤，通过小鼠荧光成像系统检测动物肿瘤大小并用以药效研究。动物来源：集萃药康生物有限公司。The mPA KPC orthotopic spontaneous pancreatic cancer model is a tumor model formed by mutating KRAS (G12D) and TP53 in mice. The isolated tumor tissue was cultured as a single cell and a cell line was formed in vitro. The cell line was labeled with green luciferase and mixed with matrix collagen and transplanted into the mouse pancreatic tissue to form an orthotopic tumor. The imaging system detects tumor size in animals and is used for drug efficacy studies. Animal source: Jicui Yaokang Biological Co., Ltd.
60只6～7周龄的C57BL/6雌性小鼠原位胰腺接种mPAKPC-luciferase细胞(集萃药康生物有限公司)，接种剂量为5×105cells/100μL/只(肿瘤细胞和基质胶按体积比4:1配比)。于接种后第6天进行活体成像，根据成像结果选取40只小鼠均分为4组，G1Vehicle组，G2西奥罗尼组，G3西达本胺组，G4西奥罗尼+西达本胺联用组，并将分组当天定义为第0天(D0)。从D0开始给药，给药剂量如表7所示。60 C57BL/6 female mice aged 6 to 7 weeks were inoculated into the pancreas in situ with mPA KPC -luciferase cells (Jicui Yaokang Biological Co., Ltd.), and the inoculation dose was 5×10 5 cells/100 μL/mouse (tumor cells and Matrigel According to the volume ratio of 4:1). In vivo imaging was performed on the 6th day after inoculation. According to the imaging results, 40 mice were selected and divided into 4 groups: G1 Vehicle group, G2 Ciopronib group, G3 Chidamide group, and G4 Ciopronib + Chidamide. Amine combined group, and the day of grouping was defined as day 0 (D0). Administration was started from D0, and the dosage was shown in Table 7.
表7各组给药剂量与方法
Table 7 Dosage and method of administration in each group
注：单药按体重调整给药体积，10μL/g×小鼠体重(g)；两个药物联合给药时，药物不能混在一起，给药时间间隔半小时，给药总体积按10μL/g×小鼠体重(g)，每个药物配制浓度提高一倍。 Note: The dosing volume of a single drug is adjusted according to body weight, 10 μL/g × mouse body weight (g); when two drugs are administered jointly, the drugs cannot be mixed together, the dosing time interval is half an hour, and the total dosing volume is 10 μL/g. ×Mouse body weight (g), the concentration of each drug preparation is doubled.
药物配制：Drug Preparation:
Vehicle组(模型组)：0.5％CMC+0.1％Tween80；Vehicle group (model group): 0.5% CMC+0.1% Tween80;
西奥罗尼组：相应质量的西奥罗尼加入到与Vehicle组相同的溶剂中，涡旋震荡成浓度0.5mg/mL和1mg/mL两种混悬液；Scioronil group: The corresponding mass of Xioronil was added to the same solvent as the Vehicle group, and vortexed to form two suspensions with concentrations of 0.5 mg/mL and 1 mg/mL;
西达本胺：溶剂为0.2％CMC，将相应质量的西达本胺加入到溶剂中涡旋震荡成浓度2mg/mL和4mg/mL两种混悬液。Chidamide: The solvent is 0.2% CMC. Add the corresponding mass of chidamide into the solvent and vortex to form two suspensions with concentrations of 2 mg/mL and 4 mg/mL.
给药后，于D3、D7、D10、D14称量小鼠体重；于D7、D14用小动物活体成像仪检测肿瘤体积大小，记录荧光值，计算TGITV(肿瘤荧光值抑制率)。After administration, the mice were weighed on D3, D7, D10, and D14; on D7 and D14, the tumor volume was detected using a small animal live imager, the fluorescence value was recorded, and TGI TV (tumor fluorescence value inhibition rate) was calculated.
TGITV，计算公式如下：
TGI TV , the calculation formula is as follows:
Vnt：编号为n的小鼠在第t天的肿瘤体积V nt : Tumor volume of mouse numbered n on day t
Vn0：编号为n的小鼠在第0天的肿瘤体积V n0 : Tumor volume of mouse number n on day 0
RTVn：编号为n的小鼠在第t天的肿瘤相对体积RTV n : relative tumor volume of mouse numbered n on day t
mean RTVtreat：给药组RTV平均值mean RTV treat : mean RTV of the dosing group
mean RTVvehicle：Vehicle组RTV平均值mean RTV vehicle : Vehicle group RTV average
实验结果以平均值±标准误差(Mean±SEM)表示。两组样本之间比较采用独立样本T检验(T-Test)，数据使用SPSS进行分析，P<0.05为具有显著性差异。作图软件为Graphpad prism。Experimental results are expressed as mean±standard error (Mean±SEM). The independent sample T test (T-Test) was used to compare the two groups of samples, and the data was analyzed using SPSS. P<0.05 was considered a significant difference. The drawing software is Graphpad prism.
2.实验结果2.Experimental results
2.1西奥罗尼单药或联用西达本胺具有显著的肿瘤抑制效果2.1 Sioronib alone or in combination with chidamide has significant tumor inhibitory effect
如下图11、12和表8所示，该肿瘤模型随着时间增长，肿瘤的荧光强度增加(G1组)，说明该模型肿瘤生长符合药效评价标准。给药第7天，西达本胺单药组和联合用药组都能显著降低肿瘤荧光值，其中联合给药组有更显著的抑制效果(表9)。给药14天后，西奥罗尼和西达本胺单药组都能显著抑制肿瘤生长，TGITV分别为49.96％和51.99％，而联合给药组具有更显著的肿瘤抑制药效，TGITV为87.06％(图12和表9)，提示联合用药能更好抑制胰腺癌的生长。As shown in Figures 11, 12 and Table 8 below, as the tumor model grows over time, the fluorescence intensity of the tumor increases (G1 group), indicating that the tumor growth of this model meets the drug efficacy evaluation standards. On the 7th day of administration, both the chidamide single-drug group and the combination group could significantly reduce the tumor fluorescence value, with the combination group having a more significant inhibitory effect (Table 9). After 14 days of administration, both the cealonib and chidamide single-drug groups could significantly inhibit tumor growth, with TGI TV of 49.96% and 51.99% respectively, while the combined administration group had a more significant tumor-inhibitory effect, with TGI TV It was 87.06% (Fig. 12 and Table 9), indicating that the combination of drugs can better inhibit the growth of pancreatic cancer.
表8不同组别肿瘤荧光值变化

Table 8 Changes in tumor fluorescence values in different groups

注：数据以Mean±SEM表示。Note: Data are expressed as Mean ± SEM.
表9不同组别肿瘤荧光值抑制率变化(TGITV)
Table 9 Changes in tumor fluorescence value inhibition rates in different groups (TGI TV )
2.2西奥罗尼单药或联合西达本胺未显著影响动物体重2.2 Sioronil alone or combined with chidamide did not significantly affect animal weight
如图13所示，动物给药期间体重有略微降低，但都未达到显著水平(<0.5％)，也不影响动物活动状态。无论是单药还是联合给药，动物体重皆在正常范围，无显著下降，说明药物剂量属于动物耐受范围之内。As shown in Figure 13, the body weight of the animals decreased slightly during the administration, but it did not reach a significant level (<0.5%), nor did it affect the animal's activity state. Whether administered alone or in combination, the body weight of the animals was within the normal range without significant decrease, indicating that the drug dose was within the tolerance range of the animals.
3.实验结论3.Experimental conclusion
西奥罗尼和西达本胺单药能显著抑制小鼠原位胰腺癌的肿瘤生长，而联合给药具有比两个单药更优的肿瘤抑制效果，且对动物体重没有显著的影响。 Ciopronib and chidamide alone can significantly inhibit the tumor growth of orthotopic pancreatic cancer in mice, while combined administration has a better tumor inhibitory effect than the two single drugs without significant impact on the animal body weight.

Claims (11)

  1. 西奥罗尼或其衍生物在制备用于预防和/或改善和/或治疗胰腺癌的药物中的用途；进一步的，所述西奥罗尼衍生物包括其可药用盐、非溶剂化晶体A、B或C。The use of Sioronil or its derivatives in the preparation of medicines for preventing and/or improving and/or treating pancreatic cancer; further, the Sioronil derivatives include pharmaceutically acceptable salts, non-solvated salts thereof, Crystal A, B or C.
  2. 西奥罗尼或其衍生物联合HDAC抑制剂在制备用于预防和/或改善和/或治疗胰腺癌的药物中的用途；进一步的，所述西奥罗尼衍生物包括其可药用盐、非溶剂化晶体A、B或C；所述HDAC抑制剂选自恩替诺特(Entinostat)、伏立诺他(Vorinostat)、帕比司他(Panobinostat)、莫西司他(Mocetinostat)、贝利司他(Belinostat)、普雷司他(Pracinostat)、罗米地辛(Romidepsin)、西达本胺(Chidamide)，或其衍生物；The use of ceopronib or its derivatives in combination with HDAC inhibitors in the preparation of drugs for preventing and/or improving and/or treating pancreatic cancer; further, the ceopronib derivatives include pharmaceutically acceptable salts thereof , non-solvated crystals A, B or C; the HDAC inhibitor is selected from Entinostat, Vorinostat, Panobinostat, Mocetinostat, Belinostat, Pracinostat, Romidepsin, Chidamide, or their derivatives;
    优选的，所述HDAC抑制剂选自西达本胺或其衍生物；Preferably, the HDAC inhibitor is selected from chidamide or its derivatives;
    进一步的，所述西达本胺衍生物包括其可药用盐、对映异构体、晶型A或晶型B。Further, the chidamide derivative includes its pharmaceutically acceptable salt, enantiomer, crystal form A or crystal form B.
  3. 西奥罗尼或其衍生物联合FAK抑制剂在制备用于预防和/或改善和/或治疗胰腺癌的药物中的用途；进一步的，所述西奥罗尼衍生物包括其可药用盐、非溶剂化晶体A、B或C；所述FAK抑制剂选自PND1186、GSK-2256098、TAE226、PF-562271、PF-431396、PF-04554878、BI-4464；The use of cealonil or its derivatives in combination with FAK inhibitors in the preparation of drugs for preventing and/or improving and/or treating pancreatic cancer; further, the cealonil derivatives include pharmaceutically acceptable salts thereof , non-solvated crystal A, B or C; the FAK inhibitor is selected from PND1186, GSK-2256098, TAE226, PF-562271, PF-431396, PF-04554878, BI-4464;
    优选的，所述FAK抑制剂选自PND1186。Preferably, the FAK inhibitor is selected from PND1186.
  4. 西奥罗尼或其衍生物用于预防和/或改善和/或治疗胰腺癌；进一步的，所述西奥罗尼衍生物包括其可药用盐、非溶剂化晶体A、B或C。Scioronil or its derivatives are used to prevent and/or improve and/or treat pancreatic cancer; further, the Xioronil derivatives include pharmaceutically acceptable salts, unsolvated crystals A, B or C thereof.
  5. 西奥罗尼或其衍生物联合HDAC抑制剂用于预防和/或改善和/或治疗胰腺癌；进一步的，所述西奥罗尼衍生物包括其可药用盐、非溶剂化晶体A、B或C；所述HDAC抑制剂选自恩替诺特(Entinostat)、伏立诺他(Vorinostat)、帕比司他(Panobinostat)、莫西司他(Mocetinostat)、贝利司他(Belinostat)、普雷司他(Pracinostat)、罗米地辛(Romidepsin)、西达本胺(Chidamide)，或其衍生物；Scioronib or its derivatives combined with HDAC inhibitors are used to prevent and/or improve and/or treat pancreatic cancer; further, the Xioronib derivatives include pharmaceutically acceptable salts thereof, nonsolvated crystals A, B or C; the HDAC inhibitor is selected from Entinostat, Vorinostat, Panobinostat, Mocetinostat, Belinostat , Pracinostat, Romidepsin, Chidamide, or their derivatives;
    优选的，所述HDAC抑制剂选自西达本胺或其衍生物；Preferably, the HDAC inhibitor is selected from chidamide or its derivatives;
    进一步的，所述西达本胺衍生物包括其可药用盐、对映异构体、晶型A或晶型B。Further, the chidamide derivative includes its pharmaceutically acceptable salt, enantiomer, crystal form A or crystal form B.
  6. 西奥罗尼或其衍生物联合FAK抑制剂用于预防和/或改善和/或治疗胰腺癌；进一步的，所述西奥罗尼衍生物包括其可药用盐、非溶剂化晶体A、B或 C；所述FAK抑制剂选自PND1186、GSK-2256098、TAE226、PF-562271、PF-431396、PF-04554878、BI-4464；Scioronil or its derivatives combined with FAK inhibitors are used to prevent and/or improve and/or treat pancreatic cancer; further, the Xioronil derivatives include pharmaceutically acceptable salts thereof, nonsolvated crystals A, B or C; The FAK inhibitor is selected from PND1186, GSK-2256098, TAE226, PF-562271, PF-431396, PF-04554878, BI-4464;
    优选的，所述FAK抑制剂为PND1186。Preferably, the FAK inhibitor is PND1186.
  7. 一种药物组合物，其包括作为活性成分的西奥罗尼或其衍生物和FAK抑制剂，以及药学上可接受的辅料；进一步的，所述FAK抑制剂选自PND1186、GSK-2256098、TAE226、PF-562271、PF-431396、PF-04554878、BI-4464；优选的，所述FAK抑制剂为PND1186。A pharmaceutical composition, which includes cealonil or its derivatives and a FAK inhibitor as active ingredients, as well as pharmaceutically acceptable excipients; further, the FAK inhibitor is selected from PND1186, GSK-2256098, TAE226 , PF-562271, PF-431396, PF-04554878, BI-4464; preferably, the FAK inhibitor is PND1186.
  8. 根据权利要求7所述的药物组合物，其特征在于：所述西奥罗尼或其衍生物的单位剂量为5-100mg，优选为10-100mg，更优选为25mg；所述PND1186的单位剂量为10-200mg，优选为20-200mg，更优选为200mg。The pharmaceutical composition according to claim 7, characterized in that: the unit dose of ceoranib or its derivative is 5-100 mg, preferably 10-100 mg, more preferably 25 mg; the unit dose of PND1186 It is 10-200 mg, preferably 20-200 mg, and more preferably 200 mg.
  9. 一种药盒，其包括权利要求8或9所述的药物组合物。A pharmaceutical kit comprising the pharmaceutical composition according to claim 8 or 9.
  10. 根据权利要求9所述的药盒，其特征在于：所述西奥罗尼或其衍生物和FAK抑制剂为具有相同或不同规格的单位制剂，所述西奥罗尼或其衍生物和所述FAK抑制剂置于同一容器中、或者分别置于不同容器中。The kit according to claim 9, characterized in that: the ceopronib or its derivatives and the FAK inhibitor are unit preparations with the same or different specifications, and the ceopronib or its derivative and the FAK inhibitor are unit preparations with the same or different specifications. The FAK inhibitors are placed in the same container or in different containers.
  11. 预防和/或改善和/或治疗胰腺癌的方法，其特征在于：向有需要的患者施用西奥罗尼或其衍生物；或者联合施用西奥罗尼或其衍生物和HDAC抑制剂；或者联合施用西奥罗尼或其衍生物和FAK抑制剂；进一步的，所述HDAC抑制剂选自恩替诺特(Entinostat)、伏立诺他(Vorinostat)、帕比司他(Panobinostat)、莫西司他(Mocetinostat)、贝利司他(Belinostat)、普雷司他(Pracinostat)、罗米地辛(Romidepsin)、西达本胺(Chidamide)，或其衍生物；所述FAK抑制剂选自PND1186、GSK-2256098、TAE226、PF-562271、PF-431396、PF-04554878、BI-4464；优选的，所述HDAC抑制剂为西达本胺或其衍生物，所述FAK抑制剂为PND1186。 A method for preventing and/or improving and/or treating pancreatic cancer, characterized by: administering ceopronib or a derivative thereof to a patient in need; or administering ceopronib or a derivative thereof and an HDAC inhibitor in combination; or Combined administration of ceoronil or its derivatives and a FAK inhibitor; further, the HDAC inhibitor is selected from the group consisting of Entinostat, Vorinostat, Panobinostat, Mo Mocetinostat, Belinostat, Pracinostat, Romidepsin, Chidamide, or derivatives thereof; the FAK inhibitor is preferably From PND1186, GSK-2256098, TAE226, PF-562271, PF-431396, PF-04554878, BI-4464; preferably, the HDAC inhibitor is chidamide or a derivative thereof, and the FAK inhibitor is PND1186 .
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