CN103739672B - 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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- CN103739672B CN103739672B CN201310748724.XA CN201310748724A CN103739672B CN 103739672 B CN103739672 B CN 103739672B CN 201310748724 A CN201310748724 A CN 201310748724A CN 103739672 B CN103739672 B CN 103739672B
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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 nutrition required for tumour and oxygen, excretion metabolism product, and the approach being distant metastasis.Therefore, block new vessel and form the means that may become and stop growth and metastasis of tumours, thus excite the extensive 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, not easily produce resistance, can long-term prescription;
the toxic side effects of the latter can be alleviated with chemicotherapy method combined utilization.
VEGF R2 (VEGFR2), also known as the acceptor (KDR) inserting territory containing kinases, belongs to receptor tyrosine kinase superfamily.VEGF R2 plays a part main in new vessel generative process.Its part VEGF is by irritation cell surface VEGFR2 activated endothelial cells, and the complicated cascade that biochemical signals occurs interacts with extracellular matrix components and soluble factor, causes lumen formation and is divided into the blood vessel of maturation.In addition, these through proliferation process, are improved the expression of cell adhesion molecule by the cell that activates, increase the secretion of proteolytic ferment, increase cell migration and invasion and attack.At present, the inhibitor of target KDR has become the study hotspot developing emerging anti-angiogenic drugs.However, the VEGF R2 tyrosine kinase polypeptide inhibitor of unripe exploitation comes 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 In vitro and in vivo activity evaluation repeatedly, can significantly suppress VEGFR2 tyrosine kinase activity.But the transformation period of aforementioned polypeptides is short, intending with the administration of clinical people is intravenous drip every day, and this brings certain misery to patient.
In bibliographical information, modifying molecular structure or transforming is solve the common method that the transformation period is shorter, need successive administration problem, wherein be most widely used with chemically modified, conventional chemical modifier has polyoxyethylene glycol (polye thylene glycol, PEG), dextran, polyamino acid, condensing model etc.PEG has nontoxic, non-immunogenicity, good water solubility feature, by FDA (FDA) accreditation as the auxiliary material of medicine and modifier.Protein drug is after PEG modifies; molecular weight increases, and the filterability of renal glomerulus reduces, and the barrier action of PEG protects protein not easily by proteolytic enzymes hydrolize; decrease the generation of neutralizing antibody, these all contribute to the prolongation of protein drug biological half-life simultaneously.The protein drug list marketing of existing multiple PEG modification at present.But PEG modifies the biologic activity that simultaneously also may affect protein, it affects size and modifier, it is relevant to modify the character of condition and protein itself.For concrete protein, its best modification need be decided by the protein of preparation PEG modification and bioactivity research.The PEG of synthesized micromolecule polypeptide modifies research and starts late, but has caused the concern of many investigators.
Summary of the invention
goal of the invention
The present invention is directed to mPEG-SC-MVIVEFCK and done further research, finding that it has therapeutic action when reducing administration frequency to kinds of tumors.
technical scheme
A polyethyleneglycol modified suppression VEGFR2 tyrosine kinase 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 suppression VEGFR2 tyrosine kinase polypeptide in preparation tumor, is characterized in that described tumour is originate from the stomach of people, skin, incidence, Tiroidina, pancreas, lungs, oesophagus, mammary gland, kidney, gall-bladder, colon/rectum, ovary, uterus, uterine cervix, prostate gland, bladder, the cancer of former/secondary of testis or sarcoma.
beneficial effect
In order to extend the transformation period of polypeptide MVIVEFCK, we adopt the polyoxyethylene glycol of different molecular weight (PEG) to modify this polypeptide, find mPEG-SC
10k-MVIVEFCK has prolong half-life, but does not affect the feature of its In vitro and in vivo 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 to the research of the kinds of tumors In vitro and in vivo activity that to have had therapeutic action to carry out a large amount of, when finding that administration frequency reduces, mPEG-SC
10k-MVIVEFCK maintains good activity to the growth of suppression kinds of tumors, has expanded its social value and economic worth.
Embodiment
The present invention relates to polypeptide to be synthesized 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, add in 96 well culture plates with 1.0 × 105, cultivate 24h, experimental port, positive drug control hole add the polyethyleneglycol modified VEGFR2 tyrosine kinase inhibitor of the Experimental agents of different concns and positive control medicine taxol respectively; 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, absorbance A value is measured, by formula growth of tumour cell inhibiting rate=(1-experimental group light absorption value/control group light absorption value) × 100% at microplate reader 620nm place.The IC50 calculating Experimental agents is 2.23 μMs.
Embodiment 2
Vigor in the body detecting polyethyleneglycol modified VEGFR2 tyrosine kinase inhibitor with tumor model.
Set up U937 tumor model, positive control medicine taxol; Blank group adds the solvent of same volume, and experimental group establishes 3 dosage: 0.75,1.5 μMs, 3 μMs mg/Kg.After 21 days, observe mouse survival quantity, calculate survival rate.Result shows, and polyethyleneglycol modified VEGFR2 tyrosine kinase inhibitor can protect small white mouse effectively, and improve the survival rate of tumor-bearing mice, survival rate reaches 89.1%.
SEQUENCE LISTING
<110> timely snow, sieve
The suppression VEGFR2 tyrosine kinase polypeptide that <120> mono-kind is polyethyleneglycol modified 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 (2)
1. a polyethyleneglycol modified suppression VEGFR2 tyrosine kinase polypeptide, is characterized in that its sequence is mPEG-SC-MVIVEFCK.
2. a kind of polyethyleneglycol modified suppression VEGFR2 tyrosine kinase polypeptide according to claim 1, is characterized in that the molecular weight of described mPEG-SC is 10000.
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| Application Number | Priority Date | Filing Date | Title |
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| 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 CN103739672A (en) | 2014-04-23 |
| CN103739672B true 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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