CN106974908B - Pharmaceutical composition and purposes containing hdac inhibitor and IRE1 inhibitor - Google Patents
Pharmaceutical composition and purposes containing hdac inhibitor and IRE1 inhibitor Download PDFInfo
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- CN106974908B CN106974908B CN201710121669.XA CN201710121669A CN106974908B CN 106974908 B CN106974908 B CN 106974908B CN 201710121669 A CN201710121669 A CN 201710121669A CN 106974908 B CN106974908 B CN 106974908B
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
The invention belongs to biomedicine fields, and in particular to a kind of application of pharmaceutical composition containing a effective amount of hdac inhibitor and a effective amount of IRE1 inhibitor and pharmaceutical composition of the present invention in the preparation treatment cancer of the esophagus, lung cancer and liver cancer.Pharmaceutical composition of the present invention achieves significant good effect in the treatment cancer of the esophagus, lung cancer and liver cancer, pharmaceutical composition of the present invention is especially applied to the treatment cancer of the esophagus, achieve significant synergistic effect, improve the curative effect of drug, it provides more choices for clinical anticancer, is suitable for a wide range of promote and apply.
Description
Technical field
The invention belongs to biomedicine fields, and in particular to the pharmaceutical composition containing hdac inhibitor and IRE1 inhibitor
And purposes.
Background technique
World Health Organization's survey report shows that global cancer condition is got worse, and the number of 20 years from now on new patients will
Increase to 15,000,000 by current annual 10000000, dead number also will increase to 1000 by annual 6,000,000 due to cancer
Ten thousand.With the improvement of living standards, the change of dietary structure, the disease incidence of the cancer of the esophagus is in rise year by year trend；Wherein primary
Liver cancer is the canceration occurred in liver cell and intrahepatic biliary epithelium cell, is one of most common malignant tumour of the mankind；Lung cancer is
Common malignant tumour is derived from bronchiolar epitheliums at different levels, is divided into cell lung cancer and non-small cell lung cancer.Though the treatment of these cancers
So based on operation, but due to the general non-evident sympton of early stage patient, in diagnosed cancer patient for the first time, much it has been
Advanced stage, lose operation excision chance, therefore non-operative treatment (such as chemotherapy) have in the comprehensive treatment of tumors it is particularly significant
Status.Chemotherapy is that proliferation, the infiltration, transfer of cancer cell are prevented using chemicals, until final one kind for killing cancer cell
Therapeutic modality.It is a kind of systemic treatment means, and operation, radiotherapy are together, and 3 big treatment means of referred to as cancer.
The anti-tumor drug listed at present is more, such as alkylating agent drug, antimetabolite, antitumor antibiotics, is immunized
Regulator etc., but the disadvantages of the big generally existing selectivity of drug is low, is more toxic, and patient does not tolerate.With to tumour
The Study on Molecular Mechanism of occurrence and development is more and more clearer, and molecular targeted therapy Several Kinds of Malignancy has received widespread attention and height
Degree is paid attention to.Molecular targeted agents selectivity is high, wide spectrum is effective, and it is current tumour that safety, which is better than cytotoxic chemotherapy agents,
The new direction of therapy field development.
Histon deacetylase (HDAC) (histone deacetylase, HDAC) is a kind of protease, to the structure of chromosome
Modification and gene expression regulation play an important role.The generation of tumour and the unconventionality expression of all polygenes especially oncogene
An important factor for closely related, and chromosome structure is controlling gene expression.Research discovery HDAC in recent years is as regulation base
Because of the key protein enzyme of transcription, the occurrence and development of dysfunction and tumour have direct relation.When HDAC overexpression and quilt
When transcription factor is raised, the normal expression of certain genes can be inhibited.It is this because HDAC activity it is excessively high caused by aberrant transcription inhibit
It is very universal in tumour, therefore HDAC becomes most potential one of the target spot of anti-tumor drug.Inhibiting the activity of HDAC can draw
It is highly acetylated to play histone, reactivates the transcription of certain tumor suppressor genes and causes multinomial downstream effect, including promotes tumour
Cell differentiation makes tumour cell retardance in G1 or G2 phase and inducing apoptosis of tumour cell, to realize its antitumor action.
Existing hdac inhibitor and other drugs are combined the example with external treatment cancer in vivo at present.Such as Chinese patent
Application CN101262878A discloses a kind of HAMLET for the treatment of cancer and the therapeutic combination of hdac inhibitor, which includes into
Divide (i) and ingredient (ii), ingredient (i) is HAMLET or its bio-modification object, and ingredient (ii) is hdac inhibitor.The composition exists
Proliferative disease is treated, shows synergistic effect as generated in those of tumour proliferative disease.But the composition is to human body
Toxic is still larger, and different degrees of adverse reaction occur in many patients after taking, it is difficult to meet the clinic for the treatment of of cancer
It needs.
Therefore, it is necessary to which providing a kind of pair of cancer cell killing has synergistic effect, while the anti-tumor drug that toxicity is low.
Summary of the invention
In order to solve the technical problems existing in the prior art, the purpose of the present invention is to provide a kind of pharmaceutical composition and
It is used for anti-tumor application, to solve disadvantages described above.
The pharmaceutical composition containing hdac inhibitor and IRE1 inhibitor that the present invention provides a kind of, comprising a effective amount of
Hdac inhibitor and a effective amount of IRE1 inhibitor.
Further, the hdac inhibitor is specifically as follows but is not limited to pabishta (LBH589), grace for Nuo Te
(MS-275) and one of Mocetinostat (MGCD0103).Preferably pabishta, No. CAS is 404950-80-7,
Structural formula is as follows:
Further, IRE1 inhibitor of the present invention is specifically as follows but is not limited to one in STF-083010 and 4 μ 8C
Kind；Preferably STF-083010, No. CAS is 307543-71-1, and structural formula is as follows:
STF-083010 is a species specificity IRE1 endonuclease enzyme inhibitor.In cell line, STF-083010 has
The cell inhibitory capacity and cytotoxicity of dosage and time dependence, STF-083010 can inhibit XBP1 montage, inhibit IRE1 α's
Endonuclease activity, but the kinase activity of IRE1 α is not influenced.The sustainable proliferation for inhibiting cell of STF-083010, co-cultures
The cell inhibitory rate of STF-083010 about 20% after 48 hours, the cell inhibitory rate about 70% of STF-083010 after co-culturing 3 days；
In MEC1 and MEC2 cell.In people's Multiple Myeloma Xenograft tumor model, STF-083010 (30mg/ is injected intraperitoneally
Kg tumour growth can) be significantly inhibited.
As the one of preferred embodiment of the present invention, pharmaceutical composition of the present invention includes pabishta and STF-
083010, the molar concentration rate of the two is 0.01~0.2: 10~80, more preferably 0.032: 60.
As presently preferred embodiment, pharmaceutical composition of the present invention includes pabishta and 4 μ 8C, and two
The molar concentration rate of person is 0.01~1: 1~50, more preferably 0.05: 5.
4 μ 8C are efficient selectivity IRE1 inhibitor, it can blocking group bottom (RIDD) close to IRE1 active site, and
The mRNA degradation inactivation that selectivity mediates Xbp1 splicing and IRE1.
As presently preferred embodiment, pharmaceutical composition of the present invention includes that grace replaces Nuo Te and STF-
083010, the molar concentration rate of the two is 0.2~1: 10~80, more preferably 0.5: 60.
As presently preferred embodiment, pharmaceutical composition of the present invention includes grace for Nuo Te and 4 μ 8C, and two
The molar concentration rate of person is 0.2~1: 1~50, more preferably 0.5: 5.
As presently preferred embodiment, pharmaceutical composition of the present invention includes Mocetinostat and STF-
083010, the molar concentration rate of the two is 1~5: 10~80, more preferably 3.0: 60.
As presently preferred embodiment, pharmaceutical composition of the present invention includes Mocetinostat and 4 μ
8C, the molar concentration rate of the two are 0.2~1: 1~50, more preferably 3.0: 5.
Pharmaceutical composition of the present invention can be used for preparing the drug of prevention and/or the various tumours for the treatment of, the tumour
Including but not limited to eat cancer, lung cancer, liver cancer.
Further, can by heretofore described pharmaceutical composition according to this field routine techniques be prepared into ejection preparation or
Heretofore described pharmaceutical composition is preferably prepared into oral preparation by oral preparation, the present invention, and the oral preparation is preferably
Oral capsule.According to dosage form, the content of pharmaceutical composition of the present invention in the formulation can in mass for 1~
99%, preferably 5~90%；The auxiliary material of this field routine can be used in the auxiliary material that preparation uses, with pharmaceutical composition of the present invention of getting along well
Object is reacted or is not influenced premised on the curative effect of drug of the present invention；The preparation method of preparation can use the system of this field routine
It is prepared by Preparation Method.
The dosage of pharmaceutical composition in the present invention according to the dosage form of administration object, administration route or drug not
It is same to carry out variation appropriate, but to guarantee that the pharmaceutical composition can reach effective blood concentration in the mammalian body
Premised on.
Compared with prior art, pharmaceutical composition of the present invention has the advantage that
Pharmaceutical composition of the present invention has significant good effect in the treatment cancer of the esophagus, lung cancer and liver cancer, especially
In terms for the treatment of the cancer of the esophagus, synergistic effect is achieved, hence it is evident that better than the one-component drug in them, and through testing table
It is bright, the effect of pabishta and STF-083010 synergy be substantially better than STF-083010 respectively with cis-platinum, 5- fluorine urine it is phonetic
The joint of pyridine, pabishta and STF-083010 drug combination are more preferable to the therapeutic effect of tumour, and toxicity is lower, reduces pair
The generation of effect achieves unexpected technical effect, provides more choices for clinical anticancer.
Detailed description of the invention
Fig. 1 shows the influence of pabishta and STF-083010 synergy to esophageal cancer cell Clone formation；
Fig. 2 shows the influence of pabishta and STF-083010 synergy to esophageal cancer cell apoptosis；
Fig. 3 shows pabishta and the influence that STF-083010 synergy grows nude mice esophageal transplanted tumors；
Fig. 4 shows that pabishta, cis-platinum, 5 FU 5 fluorouracil and STF-083010 combine to tumour cell and normal cell
Influence.
Specific embodiment:
The following describes the present invention further through the description of specific embodiments, but it is to limit of the invention that this, which is not,
System, those skilled in the art's basic thought according to the present invention can make various modifications or improvements, but without departing from this
The basic thought of invention, is all within the scope of the present invention.
The influence of embodiment 1, pabishta and STF-083010 synergy to esophageal cancer cell Clone formation
Cell is divided into control after cell is adherent overnight by human esophagus cancer cell Kyse510 cell inoculation to 6 orifice plates
Group, pabishta list medicine group, the mono- medicine group of STF-083010 and pabishta and STF-083010 combination therapies group, respectively plus
Enter corresponding culture medium or drug solution, be incubated for 7 days, detects cell plates Clone formation situation.As a result as shown in Figure 1
Interpretation of result: as can be seen from Figure 1, compared with control group and single medicine group, drug combination has cell clonal formation
There is apparent coordinate repression, drug combination group cell clone quantity and volume are minimum.
The influence of embodiment 2, pabishta and STF-083010 synergy to esophageal cancer cell apoptosis
Kyse510 is induced after combining using Flow cytometry pabishta with STF083010 exclusive use and two medicines
With the Apoptosis situation of Kyse450.By Kyse510 and Kyse450 cell respectively with every hole 2 × 105The density of a cell connects
It plants to 6 orifice plates.After cell is adherent, it is grouped and is administered by embodiment 2.After being jointly processed by 48h, digested using the pancreatin that EDTA is not added
Collect cell, 10 μ l FITC dyeing liquor room temperatures be added and are protected from light 10min, after add 5 μ l PI dyeing liquor room temperatures and be protected from light instead
10min is answered, sample then uses flow cytomery Apoptosis situation, as a result as shown in Figure 2.
Interpretation of result: independent treated the apoptosis rate point of pabishta of the Kyse510 and Kyse450 cell through 32nM
It Wei 32.3% and 35.33%；Individually treated that cell withers through STF-083010 (60 μM) for Kyse510 and Kyse450 cell
The rate of dying is respectively 3.22% and 6.87%；However, with the pabishta and STF-083010 Combined Treatment Kyse510 of above-mentioned dosage
After Kyse450 cell, apoptosis rate rises to 71.1% and 47.63% respectively.The result shows that pabishta and STF-
083010 be used in combination can significantly cause esophageal cancer cell that apoptosis occurs, and the two achieves synergistic effect.
The influence that embodiment 3, pabishta and STF-083010 synergy grow nude mice esophageal transplanted tumors
Nude mice by subcutaneous tumor formation model is constructed by inoculating with Kyse510 cell, inoculating cell amount is 5 × 106It is a every
Mouse is divided into four groups, i.e. control group, group is applied alone in pabishta, and STF-083010 is applied alone after model construction success by nude mice
Group and pabishta and STF-083010 combination therapies group, administration mode are intraperitoneal injection.It is administered 14 days, sees altogether
The growing state for examining and recording mouse tumor after administration, puts to death mouse, the subcutaneous tumor tissue of mouse is taken to be weighed and be immunized
Histochemical staining, as a result as shown in Figure 3.
Interpretation of result: compared with control group and single medicine group, drug combination significantly inhibits tumour growth, connection
It shares that medicine group tumor growth rate is most slow, and the tumor weight finally stripped is most light, illustrates that drug combination can be transplanted in the cancer of the esophagus
The growth inhibition of tumor generates synergistic effect.
The influence of embodiment 4, pabishta and STF-083010 synergy to tumour cell and normal cell
The strain of Kyse450 esophageal cancer cell, the strain of Kyse510 esophageal cancer cell, A549 lung cancer cell line, HepG2 liver cancer is thin
Born of the same parents' strain is inoculated into 96 orifice plates with HUVEC normal vascular endothelia cell with the quantity of 3000-6000, every hole cell, adherent to cell
Afterwards, blank control group, the pabishta of 32nM and 60 μM of STF-083010 and drug combination group drug (32nM pabishta is added
With 60 μM of STF-083010)；In addition, doing cis-platinum, 5 FU 5 fluorouracil in Kyse450 cell strain and joining respectively with STF-083010
Medicine is shared, is grouped as follows: control group, 1 μ g/ml cis-platinum, 60 μM of STF-083010, cis-platinum+STF-083010,4 μ g/ml5- fluorine
Uracil, 5 FU 5 fluorouracil+STF-083010, after cultivating 48h, the MTT solution that 10 μ l concentration are 5mg/ml is added in every hole, is continued
4h is cultivated, the DMSO that 100 μ l are added in the every hole of culture solution is then discarded, is rocked in being protected from light on constant speed shaking table.Object to be crystallized is sufficiently molten
Xie Hou reads OD value (wavelength 570nm, reference wavelength 630nm) in microplate reader, reads the light absorption value in every hole, calculates two medicines and closes
Cell survival and inhibiting rate after.
To the combination effect of tumour cell when evaluating two kinds of combination therapies using Jin Shi amendment type, the specific steps are,
According to growth inhibition ratio (%)=(1-OD experimental group/OD control group) × 100% formula, A medicine is calculated under certain conditions
Inhibiting rate to tumour cell is EA, and calculating B medicine is under certain conditions EB to the inhibiting rate of tumour cell, then calculates two
The inhibiting rate that person is administered in combination is EC, is calculated by the following formula drug combination index q value, q=EC/ (EB+EA-EB*EA), when
Value>1.15 q are synergistic effect, and 0.85<q<1.15 are additive effect, and q<0.85 is antagonistic effect.Referred to by above-mentioned drug combination
Several calculating further judges the final drug effect of two kinds of combination therapies.As a result it is detailed in Fig. 4.
Interpretation of result: by calculating, 32nM pabishta and 60 μM of STF-083010 drug combinations Kyse450,
Q value in Kyse510, A549 and HepG2 tumour cell is respectively 1.16,1.17,1.15,1.14；Cis-platinum and STF-083010
Q value of the drug combination in Kyse450 cell is 0.90；5 FU 5 fluorouracil and STF-083010 drug combination are thin in Kyse450
Q value in born of the same parents is 0.77.This shows 32nM pabishta and 60 μM of STF-083010 drug combinations to the cancer of the esophagus, lung cancer and liver cancer
Significant good effect is all had, the two is especially being used for esophageal cancer cell strain, is achieving the effect of collaboration, and Pa Bisi
The anti esophageal cancer effect of he and STF-083010 drug combination is used in combination better than cis-platinum, 5 FU 5 fluorouracil and STF-083010.
Claims (2)
1. use of the pharmaceutical composition containing hdac inhibitor and IRE1 inhibitor in the preparation treatment cancer of the esophagus, lung-cancer medicament
On the way, which is characterized in that include a effective amount of hdac inhibitor and a effective amount of IR E1 inhibitor；The hdac inhibitor is pa
Than taking charge of him, the IRE1 Rnase inhibitor is STF-083010, STF-083010 and pabishta in described pharmaceutical composition
Molar concentration rate be 0.032: 60.
2. purposes as described in claim 1, which is characterized in that the dosage form of described pharmaceutical composition is ejection preparation or oral system
Agent.
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| CN201710121669.XA CN106974908B (en) | 2017-03-02 | 2017-03-02 | Pharmaceutical composition and purposes containing hdac inhibitor and IRE1 inhibitor |
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| CN201710121669.XA CN106974908B (en) | 2017-03-02 | 2017-03-02 | Pharmaceutical composition and purposes containing hdac inhibitor and IRE1 inhibitor |
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| CN106974908B true CN106974908B (en) | 2019-11-12 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA3106731A1 (en) * | 2018-07-23 | 2020-01-30 | Fosun Orinove Pharmatech, Inc. | Ire1a inhibitor in combination with cancer therapeutic agent for cancer treatment |
| WO2020019107A1 (en) * | 2018-07-23 | 2020-01-30 | Fosun Orinove Pharmatech, Inc. | IRE1α INHIBITOR IN COMBINATION WITH CANCER THERAPEUTIC AGENT FOR CANCER TREATMENT |
| KR20210087972A (en) * | 2018-11-02 | 2021-07-13 | 포선 오리노브 파마테크, 인코포레이티드 | IRE1α inhibitors in combination with cancer therapeutics for the treatment of cancer |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103450077A (en) * | 2007-06-08 | 2013-12-18 | 满康德股份有限公司 | IRE-1A inhibitors |
| WO2014176348A1 (en) * | 2013-04-23 | 2014-10-30 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Inhibitors of the ire-1/xbp-1 pathway and methods of using thereof |
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2017
- 2017-03-02 CN CN201710121669.XA patent/CN106974908B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103450077A (en) * | 2007-06-08 | 2013-12-18 | 满康德股份有限公司 | IRE-1A inhibitors |
| WO2014176348A1 (en) * | 2013-04-23 | 2014-10-30 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Inhibitors of the ire-1/xbp-1 pathway and methods of using thereof |
Non-Patent Citations (1)
| Title |
|---|
| Mechanisms of Acquired Drug Resistance to the HDAC6 Selective Inhibitor Ricolinostat Reveals Rational Drug-Drug Combination with Ibrutinib;Jennifer E. Amengual等;《Clin Cancer Res》;20161219;第23卷(第12期);第3084-3096页 * |
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