CN106552265A - STING agonist and application of the IDO1 inhibitor drug combinations in antitumor - Google Patents
STING agonist and application of the IDO1 inhibitor drug combinations in antitumor Download PDFInfo
- Publication number
- CN106552265A CN106552265A CN201610444373.7A CN201610444373A CN106552265A CN 106552265 A CN106552265 A CN 106552265A CN 201610444373 A CN201610444373 A CN 201610444373A CN 106552265 A CN106552265 A CN 106552265A
- Authority
- CN
- China
- Prior art keywords
- ido1
- antitumor
- sting
- cgamp
- agonist
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- 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
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
Abstract
The invention belongs to pharmaceutical technology field, specially STING agonist and application of the IDO1 inhibitor drug combinations in antitumor.The present invention is studied and is shown, the inhibitor of IDO1（1 methyl D tryptophans）With autoimmune path STING（Interferon-stimulated gene albumen）Agonist cGAMP drug combinations there is obvious antitumor action, the antitumor good drug efficacy of the agonist cGAMP than single STING, Jing animal acute toxicity experiments show that the acute toxicity of the drug combination is low, therefore, STING agonist can be used for antitumor drug with IDO1 inhibitor drug combinations.
Description
Technical field
The present invention relates to biomedicine technical field, and in particular to a kind of autoimmune signal path key protein STING
Agonist joint indole amine -2,3- dioxygenases 1（IDO1）Application of the inhibitor in antitumor.
Background technology
Tumor is one of major disease of a class serious harm human life and health, shows as cell hyperproliferation and differentiation
It is abnormal.WHO scholarly forecasts, the year two thousand twenty population in the world tumor invasion are up to 20,000,000 people, and death toll is up to 12,000,000 people,
Tumor will become the first killer of this century mankind, constitute the threat of most serious to human survival.Pulmonary carcinoma, knot/rectal cancer, gastric cancer,
The M ＆ M of hepatocarcinoma etc. occupies the prostatitis of all kinds of malignant tumor.According to the issue of national tumor Register (in 2012
State's tumour registration annual report》Statistics, annual kainogenesis tumor cases about 3,120,000, average daily 8550 people, the whole nation is per minute to be had
6 people are diagnosed as cancer.From the point of view of disease, pulmonary carcinoma, gastric cancer, knot/rectal cancer, hepatocarcinoma and the esophageal carcinoma occupy national malignant tumor and send out
First five position of disease.With the increase year by year of Cancer Mortality and mortality rate, treating malignant tumor demand is increasing.
At present, the essential therapeutic arsenals of tumor include Drug therapy, surgical operation therapy and radiotherapy.Although with molecule
Targeted drug is that the new type antineoplastic medicine of representative is constantly emerged, and within the quite a long period, traditional cell toxicant resists
Tumor medicine still occupies leading position in the Drug therapy of tumor.Traditional cell toxicant antineoplastic agent is mainly by affecting tumor
The nucleic acid and protein structure and function of cell, directly suppresses tumor cell proliferation or inducing apoptosis of tumour cell.Although people
Many effort are made in the drug treatment of tumor, new chemotherapeutics are studied, chemotherapy regimen is improved, but therapeutic effect is still
It is undesirable.Traditional cell toxicant antineoplastic agent lacks preferable selection to tumor cell and normal cell, pernicious killing
While tumor cell, also there is infringement to the normal structure of human body, so as to cause serious systemic adverse reactions, wherein relatively more normal
The untoward reaction seen is bone marrow depression, digestive tract reaction and alopecia.So many patients cannot adhere to, or even chemotherapy is abandoned, faced
It is difficult to be expected that by increasing drug dose to obtain preferable effect on bed.These factors have had a strong impact on chemotherapeutic efficacy.
In the mammalian cell of infection, microorganism and viral DNA can have by stimulating interferon secretion induction Inner source strengths
The immunne response of power.Endoplasmic reticulum（ER）Receptor protein（STING）It is required factor to the immunne response of cytoplasmic DNA.Nearest
Research shows, is cyclized cGMP-AMP dinucleotide synzyme（cGAS）Under activation condition after with reference to DNA, endogenously it is catalyzed
The synthesis of cGAMP.CGAMP is a kind of cytoplasmic DNA sensor, and it stimulates the sensing of INF- β as second message,second messenger by STING,
The activation of mediation TBK1 and IRF-3, and then start the transcription of INF- β genes.Report recently, cGAS is in DNA conjugation conditions for restructuring
Lower catalytic cyclization cGMP-AMP dinucleotide GAMP.CGAS is also reported with reference to the crystal structure of the complex of 18bp dsDNA
Road, researchs of the cGAMP in terms of antiviral immunity have been found to.CGAMP combines STING, transcription factor IRF3 is activated and is produced
Raw interferon-β.It is exogenous to give the generation that restructuring cGAS promotes ring dinucleotide cGAMP under DNA conjugation conditions, play anti-
Virus, the effect for strengthening immunity.Also have been reported that recently, the ring dinucleotide cGAMP of external synthesis has notable antineoplastic medicine
Effect.
IDO1（Indole amine -2,3- dioxygenases 1）Tryptophan reaction in activated cell generates kynurenin.Pass in antigen
In cell and in kinds of tumors tissue, IDO1 expressions are raised extremely, and tumor cell may avoid immune by IDO1
System is removed, and produces immunologic tolerance.Research shows that the IDO1 inhibitor such as Indoximod (1- methyl Ds-tryptophan) can press down
IDO1 paths processed, and the immunosuppressant of IDO1 mediations is reversed, it is finally reached the purpose for suppressing tumour growth.At present, had very
The relevant report of many IDO1 inhibitor, the inhibitor of which part IDO1 have preferable IDO1 selectivitys and inhibitory activity, few
Number has come into clinical stage.The inhibitor of these IDO1 also results in some untoward reaction while curative effect is produced
Occur.IDO1 suppresses merely its activity only produce limited therapeutic effect as the key player in tumor immune escape,
And antitumor reaction may strengthened with other chemotherapy or immunization therapy combination.
The inhibitor for being currently in the IDO1 of clinical trial has three：NewLink Genetics companies
The Indoximod and INCB024360 of NLG919, Incyte company.INCB024360 single therapies transfering malignant tumor is in a phase
In clinical experiment, in 52 patients, there are 15 stable disease more than 8 weeks, 8 stable disease more than 16 weeks, no patient part delays
Solution.Indoximod can assess 22 patients of curative effect in one clinical trial phase of metastatic solid tumors associated with Docetaxel
In 4 part alleviate, 9 stable disease.This target spot list drug effect fruit is limited at present, still will see
Fruit how.At present, still there is no document report by the agonist of STING（Ring dinucleotide cGAMP）Combine with the inhibitor of IDO1
Using the relevant report for the treatment of tumor.
The content of the invention
The technical scheme is that to combine with the inhibitor of IDO1 there is provided the agonist of STING and preparing antineoplastic agent
Purposes in thing, there is provided the agonist of STING is combined with the inhibitor antineoplastic combination medication of IDO1.
Wherein, described drug regimen includes：The agonist of STING（cGAMP）The inhibitor of joint IDO1（1- methyl-
D-trp Indoximod）.The present invention experimental researches prove that, the agonist of STING（cGAMP）The suppression of joint IDO1
Agent（1- methyl Ds-tryptophan Indoximod）Afterwards, antitumor action can be strengthened.
In the present invention, the agonist of the STING includes but is not limited to c-AMP-GMP（cGAMP）、 c-di-GMP、 c-
Di-AMP, c-di-IMP, c-AMP-IMP, c-GMP-IMP and their derivant or any combinations thing；The inhibitor of IDO1
Including IDO1 can be suppressed（Indole amine 2,3-dioxygenase 1）Tryptophan reaction in activated cell generates the compound of kynurenin.
In the present invention, the tumor includes but is not limited to colon cancer, melanoma, gastric cancer, nonsmall-cell lung cancer, ovary
Cancer, adenocarcinoma of endometrium etc..
The invention further relates to utilize the agonist of STING to combine the antineoplastic agent prepared by the inhibitor of IDO1.
In the present invention inhibitor of the agonist joint IDO1 of STING share prepared antineoplastic agent can routinely medicine
Agent is prepared into various dosage forms, including tablet, capsule, granule, suspensoid, Emulsion, solution, syrup or injection
Deng.
In the present invention, the inhibitor of the agonist joint IDO1 of STING shares prepared antineoplastic agent and can take orally
Or injection（Including one or more in intravenous injection, intravenous drip, intramuscular injection or subcutaneous injection etc.）One kind in or
Various route of administration carry out prevention, protection or the treatment of tumor-related illness.
Specific embodiment
Present disclosure is illustrated below by embodiment.In the present invention, embodiments discussed below be in order to
The present invention is preferably illustrated, is not for limiting the scope of the present invention.
Embodiment 1：The inhibitor 1- methyl Ds-tryptophan of the agonist cGAMP and IDO1 of STING（Indoximod）'s
Prepare and purchase
CGAMP is pressed under activation condition of the literature method after with reference to DNA, by cyclisation dinucleotide synzyme（cGAS）Catalysis is closed
Into purity is more than 98%.（Pingwei Li, et al., Immunity, 2013,39 (6), 1019-1031.）.1- first
Base-D-trp（Indoximod）It is purchased from Sigma Co., USA.
Embodiment 2：The inhibitor Indoximod of the agonist cGAMP and IDO1 of STING combines for antitumor animal
Experiment
Suppression animal subcutaneous transplantation tumor grown with Indoximod antineoplastic combinations medicine using mice with tumor model inspection cGAMP
Effect and the Acute Toxicity to animal.
1st, animal
Healthy male Kunming white hybridizes the F1 generation mice of Babl/c, and 20～25g of body weight, per group of 10/cage group support are divided into 16 groups.
It is purchased from Shanghai Slac Experimental Animal Co., Ltd., the certification of fitness number（Animal quality certification number：SCXK（Shanghai）2007-
0005）.Raise in cleaning grade Animal House.
2nd, medicine
Indoximod is purchased from Sigma Co., USA, and cGAMP is prepared by above-mentioned literature method.
Experiment mice is grouped：
A groups, normal group, inoculated tumour, does not give the normal saline with drug study group equivalent.
B class groups（It is divided into 5 groups by tumor cell line classification）, negative control group, inoculated tumour,
Give the normal saline with drug study group equivalent.
C class groups（It is divided into 5 groups by tumor cell line classification）, cGAMP medicine groups, inoculated tumour,
Give 20 mg/kg of cGAMP
D class groups（It is divided into 5 groups by tumor cell line classification）, cGAMP+Indoximod drug combination groups, inoculated tumour,
Indoximod 20 mg/kg of 50 mg/kg and cGAMP are given respectively.
3rd, experimental technique
Tumor cell line
Human colon cancer cell strain Lovo, human melanoma cell strain A375, human stomach cancer cell line MNK-45, human oophoroma cell line
SK-OV-3, Human endometrial adenocarcinoma cell HEC-1-A, is purchased from Chinese Academy of Sciences's cell bank.
The foundation of tumor model Mus and intervention
Cell culture, passes on, and collects cell in the cell log phase, makes concentration for (1.0 × 107) per milliliter of cell suspension,
0.2 ml cell suspension is injected in mice right fore oxter, and (cell number is 2.0 × 106Individual/only), 10 days or so tumor length is to straight
About 5 mm of footpath, tumorigenesis success, animal are divided into 4 groups at random（A、B、C、D）, administration 1 time daily, lumbar injection, successive administration 21
My god.After 21 days, put to death mice and claim tumor weight, tumour inhibiting rate=（The average knurl weight of the average knurl weight-experimental group of negative control group）/
Average knurl weight × 100% of negative control group.
4. statistical analysiss
Data are represented with x ± s, are processed using SPSS10.0 softwares, using one factor analysis of variance（one-way ANOVA）
The significance of each group knurl weight difference, significance level a=0.05 are compared in inspection.
5. result
Be successfully prepared subcutaneous transplantation tumor model after mouse hypodermic inoculation tumor cell, the agonist cGAMP of STING it is alone or with
The inhibitor 1- methyl Ds-tryptophan of IDO1（Indoximod）Share, and the two joint is used
Compared with cGAMP is alone, effect is remarkably reinforced medicine, with more excellent antitumor action.Concrete outcome is shown in Table 1-5.
1 cGAMP of table and effects of the Indoximod to human colon cancer cell strain Lovo Mus subcutaneous transplantation tumors
（N=10, mean ± SD）
The average tumour inhibiting rate of group（%）
Negative control group-
CGAMP groups 68.4 ± 0.6
CGAMP+Indoximod groups 76.1 ± 0.4
2 cGAMP of table and effects of the Indoximod to human melanoma cell strain A375 Mus subcutaneous transplantation tumors
（N=10, mean ± SD）
The average tumour inhibiting rate of group（%）
Negative control group-
CGAMP groups 67.3 ± 0.5
CGAMP+Indoximod groups 78.0 ± 0.3
3 cGAMP of table and effects of the Indoximod to human stomach cancer cell line MNK-45 Mus subcutaneous transplantation tumors
（N=10, mean ± SD）
The average tumour inhibiting rate of group（%）
Negative control group-
CGAMP groups 65.4 ± 0.5
CGAMP+Indoximod groups 74.2 ± 0.7
4 cGAMP of table and effects of the Indoximod to human oophoroma cell line's SK-OV-3 Mus subcutaneous transplantation tumors
（N=10, mean ± SD）
The average tumour inhibiting rate of group（%）
Negative control group-
CGAMP groups 59.4 ± 0.3
CGAMP+Indoximod groups 68.2 ± 0.8
5 cGAMP of table and effects of the Indoximod to Human endometrial adenocarcinoma cell strain HEC-1-A Mus subcutaneous transplantation tumors
（N=10, mean ± SD）
The average tumour inhibiting rate of group（%）
Negative control group-
CGAMP groups 57.5 ± 0.4
CGAMP+Indoximod groups 67.8 ± 0.6
The studies on acute toxicity of 3 cGAMP of embodiment and Indoximod drug combinations
Experiment material
ICR mices 30（It is purchased from Shanghai Slac Experimental Animal Co., Ltd.'s [Quality of Experimental Animals quality certification number：
SCXK （Shanghai）2007-0005 ] ）, male and female half and half, 18～22g of body weight, animal are fed with pellet, freely ingest and drink
Water.CGAMP and Indoximod is respectively with normal saline into the solution that concentration is 200 mg/mL.
Experimental technique
ICR mices are distinguished the cGAMP and Indoximod of single intraperitoneal injection 2g/kg by body weight, mice 14 days after observation administration
Interior toxic reaction and death condition.As a result find, after injected in mice administration, mice activity is normal.After administration in 14 days, mice
There is not death, the 15th day, whole sacrifices were dissected, and each internal organs of macroscopy are showed no obvious pathological changes.
Experimental result
Above-mentioned acute toxicity testing result shows that intraperitoneal injection maximum tolerated dose MTD is not less than 2 g/Kg, illustrates cGAMP
It is low with the acute toxicity of Indoximod administering drug combinations.
Claims (6)
1.STING agonist and application of the IDO1 inhibitor drug combinations in antitumor.
2.STING agonist and application of the IDO1 inhibitor drug combinations in antitumor drug is prepared.
3.STING agonist and application of the IDO1 inhibitor combinations in antitumor drug is prepared.
4. the agonist of the STING according to claim 1-3 includes but is not limited to c-AMP-GMP（cGAMP）、 c-di-
GMP, c-di-AMP, c-di-IMP, c-AMP-IMP, c-GMP-IMP and their derivant or any combinations thing；IDO1
Inhibitor include suppress IDO1（Indole amine 2,3-dioxygenase 1）Tryptophan reaction in activated cell generates the change of kynurenin
Compound.
5.STING agonist and application of the IDO1 inhibitor drug combinations in antitumor, it is characterised in that the tumor includes
But it is not limited to colon cancer, melanoma, gastric cancer, nonsmall-cell lung cancer, ovarian cancer, adenocarcinoma of endometrium etc..
6. the antineoplastic combination medicine according to claim 1-3, it is characterised in that：Its system of unit comprising different size
The anti-tumor medicinal preparation that agent and pharmaceutically acceptable carrier are prepared into, described dosage form include tablet, capsule, granule
One or more in agent, suspensoid, Emulsion, solution, syrup or injection etc., takes oral or injection（Including vein
One or more in injection, intravenous drip, intramuscular injection or subcutaneous injection etc.）One or more route of administration in is carried out
Prevention, protection or the treatment of tumor and its directly related disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610444373.7A CN106552265A (en) | 2016-06-21 | 2016-06-21 | STING agonist and application of the IDO1 inhibitor drug combinations in antitumor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610444373.7A CN106552265A (en) | 2016-06-21 | 2016-06-21 | STING agonist and application of the IDO1 inhibitor drug combinations in antitumor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106552265A true CN106552265A (en) | 2017-04-05 |
Family
ID=58418235
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610444373.7A Pending CN106552265A (en) | 2016-06-21 | 2016-06-21 | STING agonist and application of the IDO1 inhibitor drug combinations in antitumor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106552265A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019034866A1 (en) * | 2017-08-14 | 2019-02-21 | Bicyclerd Limited | Bicyclic peptide ligand sting conjugates and uses thereof |
| WO2019069275A1 (en) * | 2017-10-05 | 2019-04-11 | Glaxosmithkline Intellectual Property Development Limited | Methods for administering sting agonists |
| US11299512B2 (en) | 2016-03-18 | 2022-04-12 | Immunesensor Therapeutics, Inc. | Cyclic di-nucleotide compounds and methods of use |
| US11787833B2 (en) | 2019-05-09 | 2023-10-17 | Aligos Therapeutics, Inc. | Modified cyclic dinucleoside compounds as sting modulators |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014179760A1 (en) * | 2013-05-03 | 2014-11-06 | The Regents Of The University Of California | Cyclic di-nucleotide induction of type i interferon |
| WO2016073738A2 (en) * | 2014-11-05 | 2016-05-12 | Flexus Biosciences, Inc. | Immunoregulatory agents |
-
2016
- 2016-06-21 CN CN201610444373.7A patent/CN106552265A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014179760A1 (en) * | 2013-05-03 | 2014-11-06 | The Regents Of The University Of California | Cyclic di-nucleotide induction of type i interferon |
| WO2016073738A2 (en) * | 2014-11-05 | 2016-05-12 | Flexus Biosciences, Inc. | Immunoregulatory agents |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11299512B2 (en) | 2016-03-18 | 2022-04-12 | Immunesensor Therapeutics, Inc. | Cyclic di-nucleotide compounds and methods of use |
| WO2019034866A1 (en) * | 2017-08-14 | 2019-02-21 | Bicyclerd Limited | Bicyclic peptide ligand sting conjugates and uses thereof |
| WO2019069275A1 (en) * | 2017-10-05 | 2019-04-11 | Glaxosmithkline Intellectual Property Development Limited | Methods for administering sting agonists |
| CN111194214A (en) * | 2017-10-05 | 2020-05-22 | 葛兰素史密斯克莱知识产权发展有限公司 | Methods of administering STING agonists |
| US11787833B2 (en) | 2019-05-09 | 2023-10-17 | Aligos Therapeutics, Inc. | Modified cyclic dinucleoside compounds as sting modulators |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103908468B (en) | Application of cyclic dinucleotide cGAMP in preparing anti-tumor medicaments | |
| CN106552265A (en) | STING agonist and application of the IDO1 inhibitor drug combinations in antitumor | |
| CN106540256A (en) | Ring dinucleotide-application of the liposome conjugated monoclonal antibodies in antitumor | |
| CN106727331A (en) | The composition of immunoliposome ring dinucleotides, preparation method and its application in antitumor | |
| CN108310378A (en) | The preparation and its application of a kind of conjuncted antitumor original new drug of novel immune | |
| CN106267213A (en) | Ring dinucleotide cGAMP application in treatment tumor drug combination | |
| CN106539757A (en) | Application of the ring dinucleotide cGAMP- liposomees in antitumor | |
| CN108892700A (en) | A kind of new antitumoral compounds and its application in preparation of anti-tumor drugs | |
| CN110063953A (en) | A kind of pharmaceutical composition for treating carcinoma of endometrium | |
| WO2019074842A1 (en) | Oncolytic cancer immunotherapies and methods of use | |
| CN108653312A (en) | The antitumor research of inhibitor of the activator joint phosphodiesterase ENPP1 of endoplasmic reticulum receptor protein STING | |
| CN111420025B (en) | Application of rubiaceae cyclic peptide compound in preparation of medicine of cGAS-STING signal pathway activator | |
| CN104557909B (en) | 3- acyloxy replaces dextrorotation deoxidation tylophorinine derivative, its preparation method and pharmaceutical composition and purposes | |
| CN105476996A (en) | Application of curcumin and afatinib for combined treatment of non-small cell lung cancer | |
| CN114939122B (en) | Combined antitumor pharmaceutical composition derived from natural plants | |
| WO2007030992A1 (en) | Medicament for the treatment of tumors and its use for manufacturing a medicament for the treatment of tumors | |
| CN106309484A (en) | Application of sulfo-(seleno) phosphate cyclic dinucleotide cGAMP in cancer-treating drug combination | |
| KR101179166B1 (en) | Novel oncolytic virus derived from vaccinia virus | |
| CN106692967A (en) | Application of cyclic dinucleotide cGAMP combined PD1 antibody (Nivolumab) in preparation of antitumor drugs | |
| CN106928298B (en) | Structural composition of cyclic dinucleotide cGAMP derivative, preparation method and application of cyclic dinucleotide cGAMP derivative in tumor resistance | |
| CN113425710A (en) | Application of chlorogenic acid in preparing medicine for treating central nervous system tumor | |
| WO2017114215A1 (en) | Use of recombinant human calcineurin b subunit | |
| CN106540255A (en) | Ring dinucleotide cGAMP combines application of the Avastin in antitumor | |
| CN106540253A (en) | The application of cGAMP and its derivant in anti-tumor vaccine is prepared | |
| CN110063989A (en) | A kind of pharmaceutical composition and preparation method thereof for treating the cancer of the esophagus |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170405 |