CN103739672A - Polyethylene glycol modified polypeptide inhibiting VEGFR2 (vascular endothelial growth factor receptor2) tyrosine kinase and application thereof - Google Patents
Polyethylene glycol modified polypeptide inhibiting VEGFR2 (vascular endothelial growth factor receptor2) tyrosine kinase and application thereof Download PDFInfo
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- CN103739672A CN103739672A CN201310748724.XA CN201310748724A CN103739672A CN 103739672 A CN103739672 A CN 103739672A CN 201310748724 A CN201310748724 A CN 201310748724A CN 103739672 A CN103739672 A CN 103739672A
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- 239000002202 Polyethylene glycol Substances 0.000 title claims abstract description 16
- 229920001223 polyethylene glycol Polymers 0.000 title claims abstract description 16
- 229920001184 polypeptide Polymers 0.000 title abstract description 13
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- 102000004196 processed proteins & peptides Human genes 0.000 title abstract description 13
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 title abstract description 9
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 title abstract description 8
- 230000002401 inhibitory effect Effects 0.000 title abstract description 4
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 title abstract 5
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 title abstract 5
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 13
- 230000005764 inhibitory process Effects 0.000 claims description 7
- 206010039491 Sarcoma Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
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- 210000000232 gallbladder Anatomy 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- YDTFRJLNMPSCFM-YDALLXLXSA-M levothyroxine sodium anhydrous Chemical compound [Na+].IC1=CC(C[C@H](N)C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 YDTFRJLNMPSCFM-YDALLXLXSA-M 0.000 claims description 2
- 210000004072 lung Anatomy 0.000 claims description 2
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- 210000002307 prostate Anatomy 0.000 claims description 2
- 210000000664 rectum Anatomy 0.000 claims description 2
- 210000002784 stomach Anatomy 0.000 claims description 2
- 210000001550 testis Anatomy 0.000 claims description 2
- 210000003932 urinary bladder Anatomy 0.000 claims description 2
- 210000004291 uterus Anatomy 0.000 claims description 2
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 claims 3
- 230000000694 effects Effects 0.000 abstract description 15
- 230000004083 survival effect Effects 0.000 abstract description 6
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- 108090000623 proteins and genes Proteins 0.000 description 8
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- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 4
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 4
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- 238000000034 method Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000004037 angiogenesis inhibitor Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
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- -1 polyoxyethylene Polymers 0.000 description 3
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- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
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- 239000003795 chemical substances by application Substances 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
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- 108091000080 Phosphotransferase Proteins 0.000 description 1
- FOADDSDHGRFUOC-DZKIICNBSA-N Val-Glu-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N FOADDSDHGRFUOC-DZKIICNBSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
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- 238000013459 approach Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
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- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the filed of medicines, and particularly relates to a polypeptide inhibiting VEGFR2 (vascular endothelial growth factor receptor2) tyrosine kinase activity and curing solid tumors. The polypeptide is modified by polyethylene glycol, the sequence of the modified polypeptide is brand-new and is as follows: mPEG-SC10k-MVIVEFCK, the modified polypeptide can be used for inhibiting the VEGFR2 tyrosine kinase activity in vitro and improving the survival rate of a tumor bearing mouse by virtue of in vivo test, thus having potential development value of new medicine.
Description
Technical field
The present invention relates to polyethyleneglycol modified VEGFR2 tyrosine kinase inhibitor and application thereof, be specifically related to have suppress VEGFR2 tyrosine kinase activity, can treat noumenal tumour polypeptide.
Background technology
Research shows, the growth of solid tumor depends on new vessel and generates, and new vessel not only can provide the needed nutrition of tumour and oxygen, excretion metabolism product, and be the approach of distant metastasis.Therefore, blocking-up new vessel forms and may become the means that stop growth and metastasis of tumours, thereby has excited the broad research to Angiogensis molecule and angiogenesis inhibitor molecule.
Compare traditional tumour and control medicine treatment, angiogenesis inhibitor great advantage is: 1. selectively acting is in vascular endothelial cell, and whole body toxic side effect is little; 2. target cell is vascular endothelial cell, and medicine easily arrives contact with it and has an effect from blood;
vascular endothelial cell without or few sudden change, be difficult for producing resistance, can long-term prescription;
can and alleviate the latter's toxic side effects with chemicotherapy method combined utilization.
VEGF R2 (VEGFR2) also claims to insert containing kinases the acceptor (KDR) in territory, belongs to receptor tyrosine kinase superfamily.VEGF R2 plays a part main in new vessel generative process.By irritation cell surface VEGFR2 activation endotheliocyte, there is complicated cascade and extracellular matrix components and the soluble factor interaction of biochemical signals in its part VEGF, causes lumen to form and be divided into ripe blood vessel.In addition, the cell that these are activated is through during proliferation process, and the expression that improves cell adhesion molecule, increases the secretion of proteolytic ferment, increases cell migration and invasion and attack.At present, the inhibitor of target KDR has become the study hotspot of the emerging anti-angiogenic drugs of exploitation.However, the VEGF R2 Tyrosylprotein kinase peptide inhibitor of ripe exploitation does not come out, and is used for the treatment of solid tumor.
MVIVEFCK is a brand-new sequence, and the research in early stage shows, this polypeptide confirms to have good tumor killing effect through inside and outside activity rating repeatedly, can significantly suppress VEGFR2 tyrosine kinase activity.Yet the transformation period of aforementioned polypeptides is short, intending is intravenous drip every day with clinical people's administration, and this has brought certain misery to patient.
In bibliographical information, molecular structure is modified or transformed is to solve the common method that the transformation period is shorter, need successive administration problem, wherein with chemically modified, be most widely used, conventional chemical modifier has polyoxyethylene glycol (polye thylene glycol, PEG), dextran, polyamino acid, poly-acid anhydrides etc.That PEG has is nontoxic, the feature of non-immunogenicity, good water solubility, auxiliary material and modifier by FDA (FDA) approval as medicine.Protein drug is after PEG modifies; molecular weight increases, and the filterability of renal glomerulus reduces, and the barrier action of PEG has protected protein to be difficult for by proteolysis enzymic hydrolysis; reduced the generation of neutralizing antibody, these all contribute to the protein drug prolongation of biological half-life simultaneously.The protein drug list marketing that existing multiple PEG modifies at present.But PEG modifies, also may affect the biologic activity of protein, its impact size is relevant with the character of modifier, modification condition and protein itself simultaneously.For concrete protein, protein and bioactivity research that its best modification need be modified by preparation PEG decide.The PEG of synthesized micromolecule polypeptide modifies research and starts late, but has caused many investigators' concern.
Summary of the invention
goal of the invention
The present invention is directed to mPEG-SC-MVIVEFCK and done further research, find that it has therapeutic action to kinds of tumors in the situation that reducing administration frequency.
technical scheme
A polyethyleneglycol modified inhibition VEGFR2 tyrosine-kinase enzyme polypeptide, is characterized in that its sequence is mPEG-SC
10k-MVIVEFCK.The molecular weight of mPEG-SC is 5000-20000.The application of polyethyleneglycol modified inhibition VEGFR2 tyrosine-kinase enzyme polypeptide in preparing medicine for treating tumor thing, is characterized in that described tumour is cancer or the sarcoma of former/secondary of the stomach that originates from people, skin, incidence, Tiroidina, pancreas, lungs, oesophagus, mammary gland, kidney, gall-bladder, colon/rectum, ovary, uterus, uterine cervix, prostate gland, bladder, testis.
beneficial effect
In order to extend the transformation period of polypeptide MVIVEFCK, we adopt the polyoxyethylene glycol (PEG) of different molecular weight to modify this polypeptide, find mPEG-SC
10k-MVIVEFCK has prolong half-life, but does not affect the feature of its inside and outside activity.The modified outcome of a polypeptide belongs to a novel molecular, often in activity, produces different effects from the molecule before modification.The present invention is directed to above-mentioned polyethyleneglycol modified VEGFR2 tyrosine kinase inhibitor mPEG-SC
10k-MVIVEFCK has therapeutic action to carry out a large amount of inside and outside activity researchs to kinds of tumors, finds in the situation of administration frequency reduction mPEG-SC
10k-MVIVEFCK has kept good activity to suppressing kinds of tumors growth, has expanded its social value and economic worth.
Embodiment
The present invention relates to polypeptide synthetic by the biochemical (Shanghai) Co., Ltd. of gill.
Embodiment 1
Polyethyleneglycol modified VEGFR2 tyrosine kinase inhibitor is to the growth of cultured tumor cells in vitro and survival IC50.
Adopt MTT colorimetry.By the U937 cell of logarithmic growth, with 1.0 * 105, add in 96 well culture plates, cultivate 24h, experimental port, positive drug control wells add respectively the polyethyleneglycol modified VEGFR2 tyrosine kinase inhibitor of the Experimental agents of different concns and positive control medicine taxol; Blank group adds the solvent of same volume.Five multiple holes are established in every hole, cultivate 48h, respectively 0h, 2h, 8h, 14h, 20h, 24h, 36h,, the every hole of 48h adds MTT, after effect 4h, add DMSO, hatch 30min, at microplate reader 620nm place, measure absorbance A value, by formula growth of tumour cell inhibiting rate=(1-experimental group light absorption value/control group light absorption value) * 100%.The IC50 that calculates Experimental agents is 2.23 μ M.
Embodiment 2
With tumor model, detect vigor in the body of polyethyleneglycol modified VEGFR2 tyrosine kinase inhibitor.
Set up U937 tumor model, positive control medicine taxol; Blank group adds the solvent of same volume, and experimental group is established 3 dosage: 0.75,1.5 μ M, 3 μ M mg/Kg.After 21 days, observe mouse survival quantity, calculate survival rate.Result demonstration, polyethyleneglycol modified VEGFR2 tyrosine kinase inhibitor can be protected small white mouse effectively, improves the survival rate of tumor-bearing mice, and survival rate reaches 89.1%.
SEQUENCE LISTING
<110> timely snow, sieve
<120> polyethyleneglycol modified inhibition VEGFR2 tyrosine-kinase enzyme polypeptide and application thereof
<130>
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 8
<212> PRT
<213> artificial sequence
<400> 1
mPEG-SC1000-Met Val Ile Val Glu Phe Cys Lys
1 5
Claims (3)
1. a polyethyleneglycol modified inhibition VEGFR2 tyrosine-kinase enzyme polypeptide, is characterized in that its sequence is mPEG-SC-MVIVEFCK.
2. a kind of polyethyleneglycol modified inhibition VEGFR2 tyrosine-kinase enzyme polypeptide according to claim 1, is characterized in that the molecular weight of described mPEG-SC is 10000.
3. the application of a kind of polyethyleneglycol modified inhibition VEGFR2 tyrosine-kinase enzyme polypeptide according to claim 1 in preparing medicine for treating tumor thing, is characterized in that described tumour is cancer or the sarcoma of former/secondary of the stomach that originates from people, skin, incidence, Tiroidina, pancreas, lungs, oesophagus, mammary gland, kidney, gall-bladder, colon/rectum, ovary, uterus, uterine cervix, prostate gland, bladder, testis.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310748724.XA CN103739672B (en) | 2013-12-31 | 2013-12-31 | Polyethylene glycol modified polypeptide inhibiting VEGFR2 (vascular endothelial growth factor receptor2) tyrosine kinase and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310748724.XA CN103739672B (en) | 2013-12-31 | 2013-12-31 | Polyethylene glycol modified polypeptide inhibiting VEGFR2 (vascular endothelial growth factor receptor2) tyrosine kinase and application thereof |
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| Publication Number | Publication Date |
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| CN103739672A true CN103739672A (en) | 2014-04-23 |
| CN103739672B CN103739672B (en) | 2015-06-10 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007069272A2 (en) * | 2005-10-21 | 2007-06-21 | Panacea Biotec Limited | Pharmaceutical composition comprising at least one anticancer drug and at least one polymer |
| CN101238149A (en) * | 2005-07-22 | 2008-08-06 | 皮埃尔法布尔制药公司 | Novel anti-IGF-IR antibodies and uses thereof |
| WO2011151412A1 (en) * | 2010-06-01 | 2011-12-08 | Pierre Fabre Medicament | Novel anti-cmet antibody |
| CN102292106A (en) * | 2008-11-25 | 2011-12-21 | 奥尔德生物制药公司 | Antibodies to IL-6 and use thereof |
-
2013
- 2013-12-31 CN CN201310748724.XA patent/CN103739672B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101238149A (en) * | 2005-07-22 | 2008-08-06 | 皮埃尔法布尔制药公司 | Novel anti-IGF-IR antibodies and uses thereof |
| WO2007069272A2 (en) * | 2005-10-21 | 2007-06-21 | Panacea Biotec Limited | Pharmaceutical composition comprising at least one anticancer drug and at least one polymer |
| CN102292106A (en) * | 2008-11-25 | 2011-12-21 | 奥尔德生物制药公司 | Antibodies to IL-6 and use thereof |
| WO2011151412A1 (en) * | 2010-06-01 | 2011-12-08 | Pierre Fabre Medicament | Novel anti-cmet antibody |
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| Publication number | Publication date |
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| CN103739672B (en) | 2015-06-10 |
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Address after: 210039 Building 2, 108 West Road South Road, Yuhuatai District, Nanjing, Jiangsu Patentee after: Neusoft Whitman Biotechnology (Nanjing) Co., Ltd. Address before: 210000 Building 2, 108 West Road South Road, Yuhuatai District, Nanjing, Jiangsu Patentee before: Wittman Biotechnology (Nanjing) Co., Ltd. |
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