CN106822905A - The medicine and purposes of inhibitor containing Survivin and IRE1 inhibitor - Google Patents
The medicine and purposes of inhibitor containing Survivin and IRE1 inhibitor Download PDFInfo
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- CN106822905A CN106822905A CN201710135740.XA CN201710135740A CN106822905A CN 106822905 A CN106822905 A CN 106822905A CN 201710135740 A CN201710135740 A CN 201710135740A CN 106822905 A CN106822905 A CN 106822905A
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- 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
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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Abstract
The invention belongs to biomedicine field, and in particular to the medicine of inhibitor containing Survivin and IRE1 inhibitor, optimal embodiment is the YM155 comprising effective dose and STF 083010.Medicine of the present invention can effectively improve the toxic and side effect problem of YM155, the combination of YM155 and STF 083010 simultaneously can make drug effect produce the effect of Synergistic in treatment lung cancer, liver cancer and the cancer of the esophagus, single medicine is substantially better than to use, this point is confirmed in antitumor action of the present invention and result of the test, especially, when molar concentration rate 0.05: 60 of YM155 and STF 083010, this synergy is very good, and the toxic and side effect of agents on normal cells is minimum.
Description
Technical field
The invention belongs to biomedicine field, and in particular to the medicine and use of inhibitor containing Survivin and IRE1 inhibitor
On the way.
Background technology
Cancer is the high mortality disease for being only second to angiocardiopathy, and global cancer patient and death are all constantly
Increase.Newly-increased cases of cancer has nearly half to appear in Asia, and in China, the newly-increased cases of cancer of China is in the world to wherein most
First.Especially in 4 kinds of malignant tumours such as liver cancer, the cancer of the esophagus, stomach cancer and lung cancer, Chinese new cases and death toll are equal
Occupy first place in the world.Although the treatment of these cancers is based on operation, due to the general non-evident sympton of early stage patient, first by
It has been much middle and advanced stage in the cancer patient for making a definite diagnosis, has lost the chance of surgery excision, therefore non-operative treatment (such as chemotherapy) swollen
There is highly important status in the complex treatment of knurl.
The antineoplastic that has listed is more at present, such as alkylating agent medicine, antimetabolite, antitumor antibiotics, immune
Conditioning agent etc., but big drug generally existing toxicity is big, the shortcomings of patient does not tolerate.Therefore, how chemotherapy is further improved
It is the problem that current clinical test is urgently researched and solved that the curative effect of medicine keeps relatively low toxicity simultaneously.
Survivin is newfound apoptosis suppression gene family member, fissional dual with regulation with apoptosis is suppressed
Function.It is except being expressed in embryonic tissue, a small amount of being expressed in can be in addition to the normal structure of self-renewing, in most of malignant tumours
Expression high in tissue.Therefore Survivin is in close relations with tumour.Due to the specificity of 26S Proteasome Structure and Function, Survivin conducts
A kind of promising target of potential tumor cells targeted therapy receives more and more extensive concern.YM155,4,9- dihydro -1- (2-
Methoxy ethyl) -2- methyl -4,9- dioxos -3- (2- pyrazines methyl) -1H- naphtho-s [2,3-D] imidazolium bromide, molecular formula
It is C20H19BrN4O3, molecular weight 443.30 synthesizes by Astellas drugmakers, and water-soluble, inside and outside can effectively suppress to wither
Die suppression protein family.It has outstanding lethality to cancer cell, but big to the toxic and side effect of human body after taking.
STF-083010, No. CAS is 307543-71-1, and molecular formula is C15H11NO3S2, molecular weight is 317.38, is a kind of
Specific IRE1 endonucleases enzyme inhibitor.In cell line, the cell that STF-083010 has dosage and time dependence presses down
Ability processed and cytotoxicity, STF-083010 can suppress XBP1 montages, suppress the endonuclease activity of IRE1 α, but not influence
The kinase activity of IRE1 α.It is smaller to normal cytotoxicity, but relatively low to the inhibiting rate of tumour cell.
At present, have not been reported combining for YM155 and STF-083010.
The content of the invention
In order to solve technical problem present in prior art, press down containing Survivin it is an object of the invention to provide one kind
The medicine and purposes of preparation and IRE1 inhibitor, make drug effect generate Synergistic after YM155 and STF-083010 composite reagents
Effect, while reducing toxic and side effect of the overall medicine to human body.
The invention provides inhibitor containing Survivin and the medicine of IRE1 inhibitor, the Survivin suppressions comprising effective dose
The IRE1 inhibitor and pharmaceutically acceptable carrier of preparation, effective dose.
Further, described Survivin inhibitor is YM155.
Further, described IRE1 inhibitor is selected from the one kind in STF-083010, APY29 and 4 μ 8C.
Further, described IRE1 inhibitor is STF-083010.
As the embodiment that the present invention is optimal.Described Survivin inhibitor is YM155, described IRE1 inhibitor
It is STF-083010.
Further, the molar concentration rate of YM155 and STF-083010 is 0.01~0.5: 10~80 in the medicine.
Further, the molar concentration rate of YM155 and STF-083010 is 0.05: 60 in the medicine.
Further, can by heretofore described pharmaceutical composition according to this area routine techniques be prepared into ejection preparation or
Heretofore described pharmaceutical composition is preferably prepared into ejection preparation by oral formulations, the present invention, and the ejection preparation is preferably
Intravenous formulations.According to dosage form, YM155 of the present invention and STF-083010 contents in the formulation can be with quality
Fraction is calculated as 0.01~90%, preferably 0.5~10%；The auxiliary material that preparation is used can be using the conventional auxiliary material in this area, with not
Premised on reacting or not influenceing the curative effect of medicine of the present invention with pharmaceutical composition of the present invention；The preparation method of preparation can be adopted
It is prepared with the conventional preparation method in this area.
The dosage of the pharmaceutical composition in the present invention according to the dosage form of administration object, method of administration or medicine not
It is same to carry out appropriate change, but to ensure that the pharmaceutical composition can reach effective blood concentration in mammalian body
Premised on.
Another object of the present invention is to provide use of the aforementioned pharmaceutical compositions in prevention and/or tumor is prepared
On the way.
Further, purposes of the aforementioned pharmaceutical compositions in prevention and/or tumor is prepared, the tumour tool
Body is but is not limited to the cancer of the esophagus, lung cancer or liver cancer.
Further, purposes of the aforementioned pharmaceutical compositions in prevention and/or tumor is prepared,
Compared with prior art, medicine of the present invention has the advantage that：
1) pharmaceutical composition component of the present invention is simple, and toxicity is low, determined curative effect, meets modern medicine study theory.
2) medicine of the present invention containing YM155 and STF-083010 can effectively improve the toxic and side effect problem of YM155, while
The combination of YM155 and STF-083010 can make drug effect produce the effect of Synergistic in treatment lung cancer, liver cancer and the cancer of the esophagus, bright
Aobvious to be used better than single medicine, this point is confirmed in antitumor action of the present invention and result of the test, especially, as YM155 and
During molar concentration rate 0.05: 60 of STF-083010, this synergy is very good, and the poison pair of agents on normal cells is made
With minimum.
Brief description of the drawings
Fig. 1 shows the influence that YM155 independent medications grow to esophageal cancer cell；
Fig. 2 shows influence of the STF-083010 independent medications to different growth of tumour cell；
Fig. 3 shows influence of the YM155 and STF-083010 drug combinations to different tumour cell forms；
Fig. 4 shows influence of the YM155 and STF-083010 drug combinations to tumour cell and normal cell；
Fig. 5 shows the influence that YM155 and STF-083010 drug combinations are formed to tumor cell clone.
Specific embodiment：
Below by way of the description of specific embodiment, the invention will be further described, but this is not to limit of the invention
System, those skilled in the art's basic thought of the invention, various modifications may be made or improves, but without departing from this
The basic thought of invention, within the scope of the present invention.
The composition of raw materials of embodiment 1, pharmaceutical composition of the present invention
Composition 1：The molar concentration rate of YM155 and STF-083010, YM155 and STF-083010 is 0.05:60.
Composition 2：The molar concentration rate of YM155 and STF-083010, YM155 and STF-083010 is 0.01:10.
Composition 3：The molar concentration rate of YM155 and STF-083010, YM155 and STF-083010 is 0.5:80.
Embodiment 2, antitumor action and experiment
Research 1：The influence that YM155 grows with STF-083010 independent medications to esophageal cancer cell
Esophageal cancer cell Eca-109 and Kyse140 is independent to YM155 or STF-083010 for detectionMedicationMedicaments insensitive
Property.
1.1 experimental techniques
By tumour cell with every hole 4-6 × 103The quantity of individual cell is inoculated into 96 orifice plates, after after cell attachment (24h), incites somebody to action
YM155 is diluted to certain gradient concentration respectively with STF-083010 medicines, and 5 multiple holes are set per concentration, point experimental group and zeroing group
Dosing.Cell viability detection is carried out using mtt assay after 48h, 10 μ l MTT solution are added per hole, continue to cultivate 4h, it is careful to absorb
Liquid in hole, it is to avoid crystal in contact hole, the DMSO of 100 μ l is added per hole, is rocked in lucifuge on constant speed shaking table.Thing to be crystallized
Fully after dissolving, OD values (wavelength 570nm, reference wavelength 630nm) is read on ELIASA, measure absorbance A value.
The computing formula of growth inhibition ratio is：Growth inhibition ratio=(1-OD experimental groups/OD control groups).According to each concentration
Inhibiting rate can map and obtain dose-effect curve, mapping software is Graphpad, and medicine is accurately calculated using Logit methods
IC50(half maximal inhibitory concentration) value, concrete outcome is shown in Fig. 1 and Fig. 2.
It will be seen from figure 1 that YM155 is to two kinds of IC of tumour cell50Value is in one than in relatively low scope, wherein
ICs of the YM155 to Eca-109 tumour cells50It it is 0.549 μM, to the IC of Kyse140 tumour cells50It is 0.057 μM, YM155 pairs
The Inhibit proliferaton effect that two kinds of tumour cells have all had.
Figure it is seen that comparatively, the toxicity of STF-083010 is smaller, IC5060 μM are all higher than, but it is alone
STF-083010 acts on weaker to inhibiting tumour cells.
Research 2：The influence that YM155 and STF-083010 drug combinations grow to esophageal cancer cell
By human tumor cells Eca-109 and Kyse140 cell with every hole 4-6 × 103The quantity of individual cell is inoculated into 96 holes
Plate, after YM155 and 60 μM of 0.0125~0.25 μM of STF-083010 after cell attachment, is added, after culture 48h, adds per hole
Enter the MTT solution that 10 μ l concentration are 5mg/ml, continue to cultivate 4h, then discard DMSO, Yu Heng that nutrient solution adds 100 μ l per hole
Lucifuge is rocked on fast shaking table.After thing to be crystallized fully dissolves, OD values (wavelength 570nm, reference wavelength are read on ELIASA
630nm), the light absorption value per hole is read, two medicines is calculated and is shared rear cell survival rate.Two kinds of medicines are evaluated using Jin Shi amendment types to join
To the combination effect of tumour cell when sharing medicine, concretely comprise the following steps, according to growth inhibition ratio=(1-OD experimental groups/OD is compareed
Group) formula, it is under certain conditions EA to the inhibiting rate of tumour cell to calculate A medicines, calculates B medicines right under certain conditions
The inhibiting rate of tumour cell is EB, then calculates the inhibiting rate of both administering drug combinations for EC, and calculating joint by below equation uses
Medicine index q values, q=EC/ (EB+EA-EB*EA), when q values>1.15 is cooperative effect, 0.85<q<1.15 is additive effect, q<
0.85 is antagonistic effect.Two kinds of final medicines of combination therapies are determined whether by the calculating of above-mentioned drug combination index
Effect.
As can be seen from Table 1 and Table 2, Combination Index q values of the YM155 and STF-083010 in selected concentration range is in 1-
Between 2.8, show that the combination effect with being added or cooperate with is used in combination.Especially 0.0125 μM YM155 and 60 μM
STF-083010 combinations achieve the effect of Synergistic human tumor cells Eca-109 and Kyse140 cell is suppressed.
Meanwhile, from figure 3, it can be seen that to through the tumour cell microscope after YM155 and STF-083010 synergy
Cell number substantially subtracts compared with independent medication after observation, it is found that the obvious shrinkage of tumour cell form generation is rounded, and combination
It is few.
Both the YM155 of table 1 and STF administering drug combinations q values gauge index growth inhibiting to Eca-109 esophageal cancer cells
Both table 2YM155 and STF administering drug combinations q values gauge index growth inhibiting to Kyse140 esophageal cancer cells
| Proportioning | Q values | Addition/collaboration/antagonism |
| YM155(0.125μM)+STF(60μM) | 1.47202 | Collaboration |
| YM155(0.05μM)+STF(60μM) | 1.56487 | It is added |
| YM155(0.025μM)+STF(60μM) | 1.52388 | Collaboration |
| YM155(0.0125μM)+STF(60μM) | 2.83256 | Collaboration |
Research 3：YM155, cis-platinum, 5 FU 5 fluorouracil and STF-083010 synergy are to tumour cell and normal cell
Influence (Fig. 4)
By in the Eca-109 cancer of the esophagus, the Kyse140 cancer of the esophagus, A549 lung cancer, HepG2 HCCs and HUVEC normal blood vessels
Chrotoplast is inoculated into 96 orifice plates with the quantity of 3000-6000, every hole cell, after after cell attachment, add control group, 0.05 μM
YM155,60 μM of STF-083010 and drug combination group；In another paving Eca-109 cells to 96 orifice plates, after cell attachment, it is right to add
It is phonetic according to group, 0.5 μ g/ml cis-platinums, 60 μM of STF-083010, cis-platinum+STF-083010,2 μ g/ml 5 FU 5 fluorouracils, 5- fluorine urine
Pyridine+STF-083010, after culture 48h, it is the MTT solution of 5mg/ml that 10 μ l concentration are added per hole, continues to cultivate 4h, is then discarded
Nutrient solution adds the DMSO of 100 μ l per hole, is rocked in lucifuge on constant speed shaking table.After thing to be crystallized fully dissolves, on ELIASA
Read OD values (wavelength 570nm, reference wavelength 630nm), read per hole light absorption value, calculating two medicines share after cell survival and
Inhibiting rate.
To the combination effect of tumour cell during using Jin Shi amendment types two kinds of combination therapies of evaluation, concretely comprise the following steps,
According to the formula of growth inhibition ratio=(1-OD experimental groups/OD control groups), A medicines are calculated under certain conditions to tumour cell
Inhibiting rate be EA, it is under certain conditions EB to the inhibiting rate of tumour cell to calculate B medicines, then calculates both administering drug combinations
Inhibiting rate be EC, by below equation calculate drug combination index q values, q=EC/ (EB+EA-EB*EA), when q values>1.15 are
Cooperative effect, 0.85<q<1.15 is additive effect, q<0.85 is antagonistic effect.Entered by the calculating of above-mentioned drug combination index
One step judges two kinds of final drug effects of combination therapies.Combine by calculating 0.05 μM of YM155 and 60 μM of STF-083010
Q value of the medication in Eca-109, Kyse140, A549 and HepG2 tumour cell is respectively 1.21,1.56,1.18,1.32；It is suitable
The q values of platinum and STF-083010 drug combinations in Eca-109 cells are 0.83；5 FU 5 fluorouracil and STF-083010 joints are used
Q value of the medicine in Eca-109 cells is 0.79.These show that YM155 and STF-083010 are used in combination tool in tumour cell
Have good synergy, and smaller to the toxicity of normal HUVEC cells, at the same with cis-platinum and STF-083010 drug combinations
Group, 5 FU 5 fluorouracil compare with STF-083010 drug combinations, and YM155 and STF-083010 is suppressing esophageal cancer cell growth
There is stronger advantage in experiment.
Research 4：The influence (Fig. 5) that YM155 and STF-083010 synergy is formed to tumor cell clone
Eca-109 and Kyse140 cells are inoculated into 6 orifice plates, after cell attachment overnight after, add control group, 0.05 μM
YM155,60 μM of STF-083010 and drug combination group medicine (0.05 μM of YM155+60 μM of STF-083010), are incubated 7 days,
Detection cell plates Clone formation situation.Result is as shown in Figure 5.
From fig. 5, it can be seen that compared with control group and single medicine group, drug combination group has obvious to cell clonal formation
Coordinate repression, drug combination group cell clone quantity and clone size be minimum.
Claims (10)
1. the medicine of inhibitor containing Survivin and IRE1 inhibitor, it is characterised in that the Survivin comprising effective dose suppresses
Agent, the IRE1 inhibitor and pharmaceutically acceptable carrier of effective dose.
2. medicine as claimed in claim 1, it is characterised in that described Survivin inhibitor is YM155.
3. medicine as claimed in claim 1, it is characterised in that described IRE1 inhibitor be selected from STF-083010, APY29 and
One kind in 4 μ 8C.
4. medicine as claimed in claim 3, it is characterised in that described IRE1 inhibitor is STF-083010.
5. medicine as claimed in claim 1, it is characterised in that described Survivin inhibitor is YM155, described IRE1
Inhibitor is STF-083010.
6. medicine as claimed in claim 5, it is characterised in that the molar concentration of YM155 and STF-083010 in the medicine
Than being 0.01~0.5: 10~80.
7. medicine as claimed in claim 6, it is characterised in that the molar concentration of YM155 and STF-083010 in the medicine
Than being 0.05: 60.
8. the medicine as described in claim 1~7 is any, it is characterised in that the medicine is made into ejection preparation or oral system
Agent.
9. the medicine as described in claim 1~8 is any prepare prevention and/or tumor in purposes.
10. purposes as claimed in claim 9, it is characterised in that the tumour is the cancer of the esophagus, lung cancer or liver cancer.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020020155A1 (en) * | 2018-07-23 | 2020-01-30 | Fosun Orinove Pharmatech, Inc. | IRE1α 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 |
| WO2020087522A1 (en) * | 2018-11-02 | 2020-05-07 | Fosun Orinove Pharmatech, Inc. | IRE1α inhibitor in combination with cancer therapeutic agent for cancer treatment |
| CN111544598A (en) * | 2020-05-12 | 2020-08-18 | 华东理工大学 | Ferritin nanoparticle loaded with Survivin double inhibitors as well as preparation method and application thereof |
| WO2021155580A1 (en) * | 2020-02-07 | 2021-08-12 | Cothera Bioscience, Inc. | Combination therapies and biomarkers for treating cancer |
| WO2023092394A1 (en) * | 2021-11-25 | 2023-06-01 | Guo Dagang | Methods and compositions for treating ewing family of tumors |
| CN116531382A (en) * | 2023-06-19 | 2023-08-04 | 中国人民解放军空军军医大学 | Application of APY29 in preparation of medicine for treating esophageal squamous carcinoma |
| US11753476B2 (en) | 2018-04-08 | 2023-09-12 | Cothera Bioscience, Inc. | Combination therapy for cancers with BRAF mutation |
| US12076399B2 (en) | 2017-06-02 | 2024-09-03 | Cothera Bioscience, Inc. | Combination therapies for treating cancers |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12076399B2 (en) | 2017-06-02 | 2024-09-03 | Cothera Bioscience, Inc. | Combination therapies for treating cancers |
| US11753476B2 (en) | 2018-04-08 | 2023-09-12 | Cothera Bioscience, Inc. | Combination therapy for cancers with BRAF mutation |
| WO2020020155A1 (en) * | 2018-07-23 | 2020-01-30 | Fosun Orinove Pharmatech, Inc. | IRE1α 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 |
| WO2020087522A1 (en) * | 2018-11-02 | 2020-05-07 | Fosun Orinove Pharmatech, Inc. | IRE1α inhibitor in combination with cancer therapeutic agent for cancer treatment |
| WO2021155580A1 (en) * | 2020-02-07 | 2021-08-12 | Cothera Bioscience, Inc. | Combination therapies and biomarkers for treating cancer |
| CN111544598A (en) * | 2020-05-12 | 2020-08-18 | 华东理工大学 | Ferritin nanoparticle loaded with Survivin double inhibitors as well as preparation method and application thereof |
| WO2023092394A1 (en) * | 2021-11-25 | 2023-06-01 | Guo Dagang | Methods and compositions for treating ewing family of tumors |
| CN116531382A (en) * | 2023-06-19 | 2023-08-04 | 中国人民解放军空军军医大学 | Application of APY29 in preparation of medicine for treating esophageal squamous carcinoma |
| CN116531382B (en) * | 2023-06-19 | 2023-10-10 | 中国人民解放军空军军医大学 | Application of APY29 in preparation of medicine for treating esophageal squamous carcinoma |
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| Publication number | Publication date |
|---|---|
| CN106822905B (en) | 2019-05-17 |
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