CN106822904A - The pharmaceutical composition and its application of inhibitor containing AKT and IRE1 inhibitor - Google Patents
The pharmaceutical composition and its application of inhibitor containing AKT and IRE1 inhibitor Download PDFInfo
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- CN106822904A CN106822904A CN201710135038.3A CN201710135038A CN106822904A CN 106822904 A CN106822904 A CN 106822904A CN 201710135038 A CN201710135038 A CN 201710135038A CN 106822904 A CN106822904 A CN 106822904A
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Abstract
The present invention relates to the pharmaceutical composition and its application in preventing and treating tumour medicine is prepared of a kind of inhibitor containing AKT and IRE1 inhibitor, described AKT inhibitor is selected from MK 2206, Perifosine, Ipatasertib or AZD5363, preferably MK 2206；Described IRE1 inhibitor is selected from STF 083010, APY29 or 4 μ 8C, preferably STF 083010.Described pharmaceutical composition is with MK 2206 and the drug combinations of STF 083010, for tumor patient provides a kind of new therapeutic scheme, growth and the cell clonal formation of tumour cell can effectively be suppressed, effect is significant is better than independent medication, with addition or cooperative effect, it is simultaneously low to the toxic and side effect of normal cell, it is safe, can be applied to prepare anti-tumor drug field.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to the drug regimen of a kind of inhibitor containing AKT and IRE1 inhibitor
Thing and its application.
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 in the synthesis of tumour
There is highly important status in treatment.Wherein, chemotherapy either staging tomography, adjuvant chemotherapy of patients or palliative chemotherapy,
Very important status is occupied in complex treatment.Conventional chemotherapeutics is how phonetic with vinorelbine, taxol, fluorine urine at present
Pyridine, cis-platinum, based on 5 FU 5 fluorouracil, its chemotherapy side effect for producing, such as n and V is stronger and to hepatic and renal function and marrow
Infringement etc., limits its application to a certain extent.
AKT signal transduction pathway is one of intracellular important signal transduction pathway, and it participates in the increasing of regulation tumour cell
Grow, survive, migrating, sticking, the process such as Tumor Angiongesis, and in various kinds of tumor (such as breast cancer, lung cancer, stomach cancer, prostatitis
Gland cancer, cervical carcinoma and hematological system tumor) in have expression high.Therefore, the molecular targeted therapy with AKT as target spot is also gradually obtained
To the attention of people.Wherein, MK-2206 is a kind of AKT1/2/3 inhibitor of high selectivity, and its Main Function is to suppress AKT
Phosphorylation, to 250 kinds, other protein kinases do not have inhibitory activity, and the research of II clinical trial phase is had been enter at present.Perifosine
(KRX-0401) be a kind of new AKT inhibitor, be the alkyl phosphate choline of a heterocycle, can targeting in Akt's
Pleckstrin homeodomains suppress the activity of AKT, show good suppression breast cancer and are lived in interior various solid tumors
Property, the research of III clinical trial phase is had been enter at present.Ipatasertib (GDC-0068) is a kind of wide spectrum AKT suppressions of high selectivity
Preparation, targeting in AKT1/2/3, be compared to it is selectively high 620 times for PKA, have been enter at present II clinical trial phase research.
AZD5363 can effectively suppress all hypotypes of AKT (AKT1/2/3) as AKT inhibitor, also have to P70S6K/PKA similar
Inhibition, it is and relatively low to ROCK1/2 inhibitory activity, the research of II clinical trial phase is had been enter at present.
Inositol requirement kinases 1 (IRE1) is a kind of transmembrane protein for being positioned at endoplasmic reticulum, participates in Non-adhesion inhibition index
(UPR) in signal path information transmission.Wherein, IRE1 α/Xbp1 paths are the important sensing pathway of UPR, and IRE1 α are by sense
Know endoplasmic reticulum pressure, make kinase region autophosphorylation and then activate nuclease, sheared in mRNA level in-site and transcribed downstream
Factor Xbp1, activates the transcription of a series of UPR related genes, so that alleviate endoplasmic reticulum pressure, can also be by non-dependent Xbp1
Approach, activate JNK, trigger cell apoptosis.STF-083010 is a species specificity IRE1 endonuclease enzyme inhibitors, is had
The cell inhibitory capacity and cytotoxicity of dosage and time dependence, STF-083010 can suppress XBP1 montages, suppress IRE1 α's
Endonuclease activity, but the kinase activity of IRE1 α is not influenceed.APY29 is IRE1 allosteric modulators, can suppress IRE1R from phosphorus
Acidifying, and activate IRE1RNase activity.And 4 μ 8C are efficient selectivity IRE1 inhibitor, it can blocking group bottom (RIDD) connect
The active site of nearly IRE1, and selectively make the mRNA degraded inactivations of Xbp1 splicings and IRE1 mediations.At present, on IRE1
The research of α/Xbp1 paths is how relevant with fat metabolism regulation and control, is seldom related to the preventing and treating of tumour.
With the progress of oncomolecularbiology, tumor cells targeted therapy has turned into the focus of tumor research,
Be played an important role in the treatment of kinds of tumors.However, the biological behaviour of most of tumour is not passed by single signal
Guiding path is arranged, but what multiple signal transduction pathway was concured, therefore drug combination is targetted for Mutiple Targets
Treatment will not be only intended to reduce or delay the appearance of drug resistance, reduce toxicity, and cancer cell is killed by multi-medicament
Synergy obtains more preferable curative effect.At present, not on AKT inhibitor and IRE1 inhibitor drug combination for antineoplastic
Correlative study is reported.
The content of the invention
To solve the problems, such as prior art, it is an object of the invention to provide a kind of pharmaceutical composition and its in preparation
Application in the medicine of anti-curing oncoma, and in particular to the pharmaceutical composition containing AKT inhibitor and IRE1 inhibitor and its system
In the medicine of standby treatment lung cancer, liver cancer, the cancer of the esophagus, intestinal cancer, stomach cancer, brain tumor, cancer of pancreas, oophoroma, breast cancer or prostate cancer
Application.
The present invention provides a kind of pharmaceutical composition, and it includes AKT inhibitor and IRE1 inhibitor.
Wherein, described AKT inhibitor is selected from MK-2206, Perifosine (KRX-0401), Ipatasertib (GDC-
Or AZD5363 0068).
Described IRE1 inhibitor is selected from STF-083010, APY29 or 4 μ 8C.
Preferably, described AKT inhibitor is MK-2206.
Preferably, described IRE1 inhibitor is STF-083010.
Preferably, described pharmaceutical composition includes MK-2206 and STF-083010.
Further, the molar concentration rate of MK-2206 and STF-083010 is 1~20 in described pharmaceutical composition:10
~60.
Preferably, the molar concentration rate of MK-2206 and STF-083010 is 5 in described pharmaceutical composition:40.
Additionally, the present invention is also claimed application of the above-mentioned pharmaceutical composition in preventing and treating tumour medicine is prepared, it is described
Tumour include but is not limited to lung cancer, liver cancer, the cancer of the esophagus, intestinal cancer, stomach cancer, brain tumor, cancer of pancreas, oophoroma, breast cancer or prostatitis
Gland cancer.
Preferably, the present invention is claimed above-mentioned pharmaceutical composition in preparation prevents and treats lung cancer, liver cancer, oesophagus cancer drug
Application.
Further, described pharmaceutical composition can be equipped with pharmaceutically acceptable additive and be made ejection preparation or oral system
Agent, preferably ejection preparation, especially intravenous formulations.
The signal path that phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT) are constituted and tumor proliferation, wither
Die, shift, attacking and angiogenesis is closely related.Used as the core of the path, the AKT of abnormal activation passes through phosphorylation downstream
Molecule (such as mTOR) promotes malignancy of tumor propagation and resistance apoptosis, and participates in regulation tumour to chemicotherapy and the sensitivity of targeted therapy
Property.Specificity suppresses AKT molecule activations can effectively block PI3K/AKT signal paths, suppress tumor proliferation, promote apoptosis.This hair
A person of good sense individually processes esophageal cancer cell strain Kyse450, Kyse510, TE-1, Eca-109, EC9706 with MK-2206, finds MK-
The growth of 2206 pairs of esophageal cancer cells has certain inhibitory action, significantly reduces cancer cell number, and it was found that MK-2206
By suppressing the phosphorylation of AKT and mTOR, the expression of p-AKT and p-mTOR is set significantly to lower, so as to effectively block PI3K/AKT/
MTOR signal paths, give full play to suppression tumor proliferation, promote apoptosis effect.
On the one hand, the present inventor observes it to the cancer of the esophagus, lung cancer, liver cancer with MK-2206 and STF-083010 drug combinations
The influence of cell and normal vascular endothelia cell, as a result finds, MK-2206 and STF-083010 drug combinations, can significantly inhibit
The survival of cancer cell, reduces the quantity of cancer cell, and effect is significant is better than that MK-2206 or STF-083010 is used alone, to oesophagus
Cancer, lung cancer, the inhibition of HCC show and preferably act synergistically, meanwhile, drug combination is to normal vascular endothelia
The toxicity of cell is smaller.
On the other hand, the present inventor has also investigated MK-2206 and STF-083010 drug combinations and esophageal cancer cell has been cloned
The influence of formation, as a result shows, compared with control group and single medicine group, drug combination has obvious association to cell clonal formation
Same inhibitory action, drug combination group cell clone quantity is minimum, while volume is also minimum, shows MK-2206 and STF-083010
Drug combination drug combination is cloned to have and preferably acted synergistically to suppression esophageal cancer cell.
Compared with prior art, advantage of the invention is that：
The present invention provides a kind of pharmaceutical composition for anti-curing oncoma, specially by AKT inhibitor and IRE1 inhibitor
It is applied in combination, more specifically with MK-2206 and STF-083010 drug combinations, for tumor patient provides a kind of new treatment side
Case, described MK-2206 and STF-083010 drug combinations can effectively suppress growth and the cell clonal formation of tumour cell,
Effect is significant is better than independent medication, safe while low to the toxic and side effect of normal cell with being added or cooperative effect,
Can be applied to prepare anti-tumor drug field.
Brief description of the drawings
Fig. 1 MK-2206 are used alone the influence to esophageal cancer cell growth.
Fig. 2 MK-2206 are used alone the influence to esophageal cancer cell form.
Fig. 3 MK-2206 are used alone the influence to esophageal cancer cell mTOR/AKT paths.
The influence that Fig. 4 MK-2206 grow with STF-083010 synergy to esophageal cancer cell.
Fig. 5 MK-2206 and influence of the STF-083010 synergy to esophageal cancer cell form.
Fig. 6 MK-2206 and combination effect analysis of the STF-083010 synergy to esophageal cancer cell.
Fig. 7 MK-2206, cis-platinum, 5 FU 5 fluorouracil and STF-083010 synergy are to tumour cell and normal cell
Influence.
Fig. 8 MK-2206 and influence of the STF-083010 synergy to esophageal cancer cell Clone formation.
Specific embodiment
The present invention is further described below by way of specific embodiment, but the present invention is not limited only to following examples.
The influence that embodiment 1MK-2206 grows after individually processing to esophageal cancer cell
Detection Kyse450, Kyse510, TE-1, Eca-109, EC9706 esophageal cancer cell first individually makes to MK-2206
Drug susceptibility.
1st, experimental technique
Tumour cell is inoculated into 96 orifice plates with the quantity of 4000-6000, every hole cell, after after cell attachment (24h),
By MK-2206 drug dilutions into certain gradient concentration, 5 multiple holes are set per concentration, be divided into experimental group and zeroing group dosing.After 48h
Cell viability detection is carried out using mtt assay, 10 μ l MTT solution are added per hole, continue to cultivate 4h, it is careful to absorb liquid in hole, keep away
Crystal in contact-free hole, the DMSO of 100 μ l is added per hole, is rocked in lucifuge on constant speed shaking table.After thing to be crystallized fully dissolves,
OD values (wavelength 570nm, reference wavelength 630nm) is read on ELIASA, absorbance A value is measured.
The computing formula of growth inhibition ratio is：Growth inhibition ratio (%)=(1-OD experimental groups/OD control groups) × 100%.
Inhibiting rate according to each concentration can map and obtain dose-effect curve, and mapping software is Graphpad, accurately be counted using Logit methods
Calculate the IC of medicine50(half maximal inhibitory concentration) value.Concrete outcome is shown in Fig. 1 and Fig. 2.
It will be seen from figure 1 that MK-2206 to esophageal cancer cell strain Kyse450, Kyse510, TE-1, Eca-109,
The IC of EC970650Value is respectively 14.3,12.4,9.4,7.6 and 11.5, shows that growths of the MK-2206 to esophageal cancer cell has
Certain inhibitory action.From figure 2 it may also be seen that MK-2206 acts solely on esophageal cancer cell strain Kyse450, Kyse510
Afterwards, cell number is significantly reduced.
Embodiment 2MK-2206 is used alone the influence to esophageal cancer cell mTOR/AKT paths
Using Western blot methods detection individually processed through MK-2206 and Combined Treatment after esophageal cancer cell
The expression of the intracellular mTOR/AKT pathway associated proteins of Kyse450 and Kyse510.First by Kyse450 and Kyse510 cells
Respectively with every hole 2 × 105The density of individual cell is seeded to 6 orifice plates.After after cell attachment, it is administered by embodiment 1.After treatment 48h,
Each group cell holoprotein is collected respectively.First through SDS electrophoresis after, by protein delivery to pvdf membrane, the closing of 5% skimmed milk power room temperature
1h, the corresponding primary antibody of the albumen of detection, 4 DEG C of overnight incubations needed for being incubated.24h reclaims primary antibody, cleans 3 times with TBST, every time
5min, is incubated secondary antibody afterwards, is incubated at room temperature 1h.Cleaned with TBST 3 times afterwards, each 5min, ECL developments, are as a result shown in Fig. 3 afterwards.
From figure 3, it can be seen that in Kyse450 and Kyse510 cells, after individually being processed with MK-2206, p-AKT and
The expression of p-mTOR is significantly lowered, and illustrates that MK-2206 can suppress the phosphorylation of AKT and mTOR, makes the table of p-AKT and p-mTOR
Up to significantly downward, so as to effectively block PI3K/AKT/mTOR signal paths, suppression tumor proliferation is given full play to, promote apoptosis effect
Really.
The influence that embodiment 3MK-2206 grows with STF-083010 synergy to esophageal cancer cell
Human esophagus cancer cell Kyse450 and Kyse510 cell are inoculated into 96 with the quantity of 4000-6000, every hole cell
Orifice plate, after 5 μM of concentration MK-2206 and 40 μM of concentration STF-083010 after cell attachment, are added, after culture 48h, 10 is added per hole
μ l concentration is the MTT solution of 5mg/ml, continues to cultivate 4h, then discards the DMSO that nutrient solution adds 100 μ l per hole, is shaken in constant speed
Lucifuge is rocked on bed.After thing to be crystallized fully dissolves, OD values (wavelength 570nm, reference wavelength 630nm) is read on ELIASA,
The light absorption value per hole is read, two medicines is calculated and is shared rear cell survival rate.Synergy multi-stress is carried out with CompuSyn softwares
(Combination Index, CI) is analyzed, and as a result sees Fig. 4.And by 5 μM of concentration MK-2206 of micro- sem observation and 40 μM of concentration
STF-083010 cooperates with the change of esophageal cancer cell cellular morphology, as a result such as Fig. 5.
As shown in figure 4,5 μM of concentration MK-2206 and 40 μM of concentration STF-083010 are used in combination with combination effect well
Really.As can be seen from Figure 5, cancer cell number is significantly reduced after the combination of the medicines of MK-2206 and STF-083010 two, cellular morphology compared with normal group and
Independent medication group is compared without significant change.
CI values represent complex indexes during Combined effects, and CI values are less than 1, represent medicine respectively equal to and more than 1
Thing synergy, synergistic effect and antagonism.From fig. 6, it can be seen that MK-2206 and STF-083010 joins to esophageal cancer cell
When conjunction is used, substantially all in the range of less than 1, particularly Kyse450 shows that MK-2206 and STF-083010 exist to its CI value
It is used in combination in amount ranges of the invention with synergy well.
Embodiment 4MK-2206, cis-platinum, 5 FU 5 fluorouracil and STF-083010 synergy are thin to tumour cell and normally
The influence of born of the same parents
By in the Kyse450 cancer of the esophagus, the Kyse510 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, 5 μM
MK-2206 and 40 μM of STF-083010 and drug combination group medicine；Another paving cell Kyse450, is added as follows
Medicine：It is control group, 5 μM of MK-2206,40 μM of STF-083010, MK-2206+STF-083010,1 μ g/ml cis-platinums (CDDP), suitable
Platinum (CDDP)+STF-083010,4 μ g/ml 5 FU 5 fluorouracils (5-FU), 5 FU 5 fluorouracil (5-FU)+STF-083010, culture
After 48h, it is the MTT solution of 5mg/ml that 10 μ l concentration are added per hole, continues to cultivate 4h, then discards nutrient solution and 100 μ are added per hole
The DMSO of l, rocks in lucifuge on constant speed shaking table.After thing to be crystallized fully dissolves, read on ELIASA OD values (wavelength 570nm,
Reference wavelength 630nm), the light absorption value per hole is read, cell survival and inhibiting rate after two medicines are shared are calculated, as a result see Fig. 7.
As shown in fig. 7, YM155 and STF-083010 are applied in combination with good combined effect in tumour cell, and
Combined with STF-083010 better than cis-platinum, 5 FU 5 fluorouracil, and it is smaller to the toxicity of normal HUVEC cells.
Influence of embodiment 5MK-2206 and the STF-083010 drug combination to esophageal cancer cell Clone formation
Human esophagus cancer cell Kyse450 and Kyse510 cell is inoculated into 6 orifice plates, after cell attachment overnight after, by cell
It is divided into the mono- medicine group of control group, MK-2206, the mono- medicine groups of STF-083010 and MK-2206 and STF-083010 combination therapies groups,
Corresponding culture medium or drug solution are separately added into, are incubated 7 days, detect cell plates Clone formation situation.Result such as Fig. 8 institutes
Show, compared with control group and single medicine group, drug combination has obvious coordinate repression to cell clonal formation, and joint is used
Medicine group cell clone quantity is minimum, while volume is also minimum.
The above is only the preferred embodiment of the present invention, it is noted that it is right that above-mentioned preferred embodiment is not construed as
Limitation of the invention, protection scope of the present invention should be defined by claim limited range.For the art
For those of ordinary skill, without departing from the spirit and scope of the present invention, some improvements and modifications can also be made, these change
Enter and retouch and also should be regarded as protection scope of the present invention.
Claims (10)
1. a kind of pharmaceutical composition, it is characterised in that described pharmaceutical composition includes AKT inhibitor and IRE1 inhibitor.
2. pharmaceutical composition according to claim 1, it is characterised in that described AKT inhibitor be selected from MK-2206,
Perifosine, Ipatasertib or AZD5363.
3. pharmaceutical composition according to claim 1, it is characterised in that described IRE1 inhibitor is selected from STF-
083010th, APY29 or 4 μ 8C.
4. pharmaceutical composition according to claim 2, it is characterised in that described AKT inhibitor is MK-2206.
5. pharmaceutical composition according to claim 3, it is characterised in that described IRE1 inhibitor is STF-083010.
6. pharmaceutical composition according to claim 1, it is characterised in that described pharmaceutical composition includes MK-2206
And STF-083010.
7. pharmaceutical composition according to claim 6, it is characterised in that in described pharmaceutical composition MK-2206 and
The molar concentration rate of STF-083010 is 1~20:10~60.
8. pharmaceutical composition according to claim 7, it is characterised in that in described pharmaceutical composition MK-2206 and
The molar concentration rate of STF-083010 is 5:40.
9. the application according to any described pharmaceutical compositions of claim 1-8 in preventing and treating tumour medicine is prepared.
10. application according to claim 9, it is characterised in that described tumour be lung cancer, liver cancer, the cancer of the esophagus, intestinal cancer,
Stomach cancer, brain tumor, cancer of pancreas, oophoroma, breast cancer or prostate cancer.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020019107A1 (en) * | 2018-07-23 | 2020-01-30 | Fosun Orinove Pharmatech, Inc. | IRE1α INHIBITOR IN COMBINATION WITH CANCER THERAPEUTIC AGENT FOR CANCER TREATMENT |
| WO2020020155A1 (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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1934072A (en) * | 2004-01-30 | 2007-03-21 | 派普林生物脂股份有限公司 | Therapeutic and carrier molecules |
| CN102015606A (en) * | 2007-06-08 | 2011-04-13 | 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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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1934072A (en) * | 2004-01-30 | 2007-03-21 | 派普林生物脂股份有限公司 | Therapeutic and carrier molecules |
| CN102015606A (en) * | 2007-06-08 | 2011-04-13 | 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 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020019107A1 (en) * | 2018-07-23 | 2020-01-30 | Fosun Orinove Pharmatech, Inc. | IRE1α INHIBITOR IN COMBINATION WITH CANCER THERAPEUTIC AGENT FOR CANCER TREATMENT |
| WO2020020155A1 (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 |
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| CN106822904B (en) | 2019-10-25 |
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