CN112386707A - Tumor-targeted polypeptide drug conjugate and preparation method thereof - Google Patents

Tumor-targeted polypeptide drug conjugate and preparation method thereof Download PDF

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CN112386707A
CN112386707A CN201910766583.1A CN201910766583A CN112386707A CN 112386707 A CN112386707 A CN 112386707A CN 201910766583 A CN201910766583 A CN 201910766583A CN 112386707 A CN112386707 A CN 112386707A
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fmoc
tumor
polypeptide
drug conjugate
tumor targeting
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CN112386707B (en
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魏敏杰
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Shenyang Yijian Life Technology Co.,Ltd.
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Liaoning Medical Diagnosis And Treatment Technology Research And Development Center Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a preparation method and application of a polypeptide drug conjugate with tumor targeting, wherein the structure of the polypeptide drug conjugate with tumor targeting comprises the following steps: tumor targeting peptide WA1, non lytic linker and cytotoxic antineoplastic drug; the preparation method of the tumor targeting polypeptide drug conjugate (PDC-WA 1) adopts Fmoc solid phase synthesis. The method mainly comprises the following steps: Fmoc-Ala-Wang resin is used as a raw material, after tumor targeting polypeptide is synthesized, the tumor targeting polypeptide is sequentially connected with Fmoc-Acp-OH and chlorambucil, and purification is carried out by HPLC, so that the tumor targeting polypeptide drug conjugate with anti-tumor activity is obtained. The method has the advantages of low production cost, low environmental pollution, few reaction byproducts, low purification difficulty and simple reaction operation.

Description

Tumor-targeted polypeptide drug conjugate and preparation method thereof
Technical Field
The invention relates to a preparation method of a polypeptide drug conjugate with tumor targeting.
Background
The solid phase synthesis technology and the genetic engineering technology of the polypeptide are developed rapidly, and the research and development of the polypeptide medicine are continuously heated. There are over 100 polypeptide drugs approved for sale worldwide, and about 200 polypeptides are in clinical research. In the international research and development of polypeptide drugs, antitumor polypeptides account for about 21% of the market, and the polypeptide drugs in China mainly focus on the fields of immunity assistance, gastrointestinal hemostasis and the like. Because the incidence and mortality of the tumor are high, the targeted therapy has special significance. The polypeptide medicine has the characteristics of high selectivity, strong biological activity, low toxic and side effects and the like, so the tumor polypeptide medicine is an important component of future antitumor medicines.
The research and development of the tumor polypeptide drugs in China are basically in the initial stage, the industrialization of the anti-tumor polypeptide drugs is limited by technical conditions and synthesis equipment, and the technical field of novel peptides in China is almost in the blank stage. The research of the tumor targeting polypeptide drug conjugate belongs to a novel peptide technology, and is helpful for improving the curative effect of the tumor targeting polypeptide drug. However, the research difficulty of the anti-tumor polypeptide drug conjugate is relatively high, and mainly embodies that a proper connector is needed to ensure that the polypeptide part can be effectively coupled with the cytotoxic drug while having tumor targeting. Meanwhile, the tumor targeting polypeptide drug conjugate can be obtained only by developing the preparation technology of the novel peptide antitumor drug.
Because the tumor targeting peptide drug conjugate has selectivity on autologous cells and tumor cells, the defects of large toxic and side effects and easy generation of drug resistance of common chemotherapeutic drugs can be overcome. Therefore, the research of tumor-targeted polypeptide drug coupling is urgently needed, and the tumor-targeted polypeptide drug coupling has the characteristics of tumor specificity, safety and difficult drug resistance generation, so that the future development space in China is determined to be rapidly expanded.
Disclosure of Invention
The invention aims to design and synthesize a tumor-targeted polypeptide drug conjugate and provides a preparation method thereof.
The tumor targeting peptide can specifically recognize tumor blood vessels or tumor-related receptors so as to realize the targeting of the tumor targeting peptide. The development of the related technology for anti-tumor research has enabled the discovery of tumor-targeting peptides. Based on the preliminary work of the subject group, the tumor targeting dodecapeptide WA1 (WNPLLLTRLLPA) obtained by screening by using a phage display technology is used for designing a tumor targeting polypeptide drug conjugate.
The invention provides a tumor targeting polypeptide drug conjugate, which consists of the following parts:
(1) a tumor targeting polypeptide moiety; (2) a connector portion; (3) a cytotoxic antitumor drug.
The tumor targeting peptide part is WA1 (WNPLLLTRLLPA), or a polypeptide sequence or a polypeptide derivative with 1-3 amino acids substituted, deleted or inserted.
The connector part is a non-cracking connector, a non-ring chain formed by connecting carbon atoms through covalent bonds is used as a carbon frame, and the structure is as follows:
Figure RE-807751DEST_PATH_IMAGE001
；
wherein n = 4-6, specifically, the invention uses 6-aminocaproic acid as a connecting reagent to form a connector part.
The cytotoxic antitumor drug can be selected from nitrogen mustard, chlorambucil, adriamycin, paclitaxel, cisplatin and the like, and is suitable for the invention.
The representative compound of the tumor targeting polypeptide drug conjugate is (PDC-WA 1), the tumor targeting peptide part is WA1, the connecting reagent is 6-aminocaproic acid, the cytotoxic antitumor drug is chlorambucil, and the structural formula is as follows:
Figure RE-DEST_PATH_IMAGE002
the tumor targeted polypeptide drug conjugate has a targeting effect on tumor cells, and can effectively kill the tumor cells.
The invention provides a preparation method of the tumor-targeted polypeptide drug conjugate.
A solid phase synthesis method of a tumor targeting polypeptide drug conjugate (PDC-WA 1) comprises the following steps:
step 1, adopting Fmoc solid phase synthesis strategy to mix Fmoc-Ala-Wang resin with Fmoc-Pro-OH, Fmoc-Leu-OH and Fmoc-Arg (R)1)-OH 、Fmoc-Thr(tBu)-OH、Fmoc-Asn(R1)-OH、Fmoc-Trp(R1) -OH is connected according to the amino acid sequence of the tumor targeting peptide WA 1;
and 2, removing the Fmoc protecting group at the N end of the tumor targeting peptide, and connecting the tumor targeting peptide with Fmoc-Acp-OH to obtain WA 1-linker-Fmoc bonded on the resin.
And 3, removing an Fmoc protecting group from the obtained WA 1-linker-Fmoc, and connecting the obtained WA 1-linker-Fmoc with chlorambucil through a chemical reaction.
Step 4, cutting PDC-WA1 from the resin by using a cracking reagent, and precipitating by using anhydrous ether; separating and purifying by preparative HPLC, and lyophilizing to obtain the final product.
In the step 1, Fmoc-Ala-Wang resin (bonding amount is 0.237 mmol/g) and a reagent for removing Fmoc is Pip and DMF in a volume ratio (Pip: DMF = 1: 10-1: 1). The polypeptide coupling agent is DIC/HOAt, and the condensation reaction temperature is maintained at 0-30 ℃.
In the step 1, the Fmoc-Arg (R)1)-OH 、Fmoc-Asn(R1)-OH、Fmoc-Trp(R1) R of-OH1H, Trt, tBu, Boc, Pbf, etc.
In the step 2, after Fmoc protecting groups are removed from Fmoc-WA1-Wang resin, the Fmoc protecting groups are reacted with DIC, HOAt and Fmoc-Acp-OH with the molar weight of 1-5 times that of the Fmoc protecting groups. The reaction is required to be carried out in an ultrasonic reactor, a microwave reactor and a polypeptide synthesizer reactor.
In the step 3, after removing the Fmoc protecting group from Fmoc-linker-WA1-Wang resin, carrying out the Fmoc protecting group and 1-5 times of DIC, HOAt and chlorambucil in a molar amount in an ultrasonic reactor, a microwave reactor and a polypeptide synthesizer reactor.
In the step 4, the cleavage peptide resin reagent is 95% TFA water solution, the reaction is carried out for 1-2 h at room temperature, and crude peptide is obtained through precipitation and centrifugal precipitation. Purification was performed using high performance liquid chromatography, using a C18 preparative column with mobile phase V (0.1% TFA in acetonitrile): v water = 2: 8-8: 2; the flow rate is: 8 ml/min; detecting wavelength at 230nm, eluting to obtain PDC-WA1 fraction, and lyophilizing to obtain the final product.
The tumor-targeted polypeptide drug conjugate (PDC-WA 1) provided by the invention is applied to the preparation of drugs for treating tumors, wherein the tumors comprise breast cancer, ovarian cancer, liver cancer, prostate cancer, lymphoma, melanoma and the like.
The medicinal preparation with the tumor-targeted polypeptide drug conjugate (PDC-WA 1) as an active ingredient comprises various forms such as lyophilized powder for injection, tablet, liposome, nanometer preparation, etc.
Some of the abbreviations commonly used in the present invention have the following meanings:
fmoc is fluorenylmethyloxycarbonyl;
Fmoc-AA: a fluorenylmethyloxycarbonyl-protected amino acid;
DIC: n, N' -diisopropylcarbodiimide;
HOAt: 1-hydroxy-7-azobenzotriazol;
6-HOAt: 1-hydroxy-6-azobenzotriazol;
HOBt: 1-hydroxybenzotriazole;
6-Cl-HOBt: 6-chloro-1-hydroxybenzotriazole;
pro: (ii) proline;
leu: leucine;
ala: alanine;
arg: arginine;
thr: threonine;
asn: asparagine;
trp: tryptophan;
Fmoc-Acp-OH: fluorenylmethoxycarbonyl-6-aminocaproic acid;
DMF: n, N-dimethylformamide;
DCM: dichloromethane;
TFA: trifluoroacetic acid;
and Pip: piperidine;
trt: a trityl group;
tBu: a tertiary butyl group;
pbf: 2,2,4,6, 7-pentamethyldihydrobenzofuran;
boc is tert-butyloxycarbonyl.
The invention designs and synthesizes a novel polypeptide antitumor drug which can specifically target tumor cells. Breaks through the key technology of the stable assembly of the tumor-targeted peptide conjugate drug, realizes the stable connection of the tumor-targeted polypeptide and the traditional chemotherapeutic drug, and simultaneously has the curative effect of targeting anti-tumor. The tumor targeting polypeptide is linked with traditional chemotherapeutic drugs by a non-cleavable connecting chain, and meanwhile, a proper interval length is provided to keep the combination configuration of the tumor targeting polypeptide and a tumor target. Overcomes the defects of large toxic and side effects, no tumor targeted killing, easy generation of drug resistance and the like of the traditional chemotherapeutic drugs. Establishes a polypeptide solid phase synthesis route and solves the technical core problem of the chemical synthesis of the tumor targeting peptide coupling drug.
Drawings
FIG. 1 is a mass spectrum of WA 1-linker.
FIG. 2 is a mass spectrum of PDC-WA 1.
Detailed Description
The invention is illustrated below with reference to specific examples.
Example 1 Synthesis of Fmoc-WA1-Wang resin.
Fmoc-Ala-Wang resin (substitution 0.237 mmol/g, 0.711 mmol) was added to the solid phase reaction tube, and 25 ml DMF was added to swell for 20 min. The Fmoc-protecting group removal reagent was 20% Pip in DMF and the amino acid condensing agent was HOAt (0.387 g, 2.844 mmol) and DIC (0.440 ml, 2.844 mmol). After Fmoc-Pro-OH (0.959 g, 2.844 mmol) was added for 2 h, the extension of one amino acid was completed by 3 washes with DMF. Fmoc-Leu-OH (1.005 g, 2.844 mmol), Fmoc-Arg (pbf) -OH (1.845 g, 2.844 mmol), Fmoc-Thr (tBu) -OH (1.130 g, 2.844 mmol), Fmoc-Asn (Trt) -OH (1.697 g, 2.844 mmol), Fmoc-Trp (Boc) -OH (1.498 g, 2.844 mmol) were added in sequence WA1 according to the above reaction cycle of amino acid condensation, and the reaction WAs carried out, washed 2 times with DMF, washed twice with DCM, and dried to obtain Fmoc-Trp (Boc) -Trt-Pro-Leu-Leu-Leu-Thr (tBu) -Arg (pbf) -Leu-Pro-Ala-Wang, i.e.e., Fmoc-WA1-Wang resin.
Example 2 Synthesis of Fmoc-linker-WA1-Wang resin.
After removing the Fmoc protecting group from the obtained Fmoc-WA1-Wang resin by using a 20% Pip solution in DMF, HOAt (0.387 g, 2.844 mmol), DIC (0.440 ml, 2.844 mmol) and Fmoc-Acp-OH (1.005 g, 2.844 mmol) are added into an ultrasonic reactor for reaction for 45min, the reaction end point is judged by Kaiser detection, the reaction solution is drained, and the Fmoc-linker-WA1-Wang resin is obtained by washing 2 times with DMF. (a small amount of the product WAs treated with a peptide cleavage reagent to obtain WA 1-linker, and mass spectrometric detection WAs carried out, the result is shown in FIG. 1.
Example 3 Synthesis of PDC-WA 1.
Fmoc-WA1-Wang resin WAs also deprotected using 20% Pip in DMF and HOAt (0.387 g, 2.844 mmol), DIC (0.440 ml, 2.844 mmol) and chlorambucil (0.865 g, 2.844 mmol) were added and reacted in an ultrasonic reactor for 1 h, DMF WAs washed 2 times and the resin WAs shrunk with methanol. Peptide cleavage reagent 95% aqueous TFA was added and the reaction was carried out for 1.5h in ice bath. Filtering, adding the filtrate into anhydrous ether, and centrifuging to obtain crude peptide. The crude peptide was dissolved, purified by HPLC, and then lyophilized to give 0.449 g (yield: 35%) of the product, which was subjected to mass spectrometric detection, and the results are shown in FIG. 2.
Example 4 study of antitumor Effect of tumor targeting polypeptide drug conjugate (PDC-WA 1).
The cytotoxicity of PDC-WA1 WAs evaluated by using two ovarian cancer cell lines, OVCAR-3 (ovary; ER +) and A2780 (ovary; ER). Chlorambucil was used as a control. Cell proliferation was measured colorimetrically using MTT (3- (4, 5-dimethylthiazol-2-yl) -phenyltetrazolium bromide). Tumor cell lines were added to 96-well tissue culture dishes at 5% CO2Culturing for 24 h in the atmosphere. The cells were cultured for an additional 48 hours with the addition of PDC-WA1, chlorambucil and PBS. The plates were treated for 3.5 h by the MTT method and SDS spiking solution (HCl 0.010M, sodium dodecyl sulfate solution 10%) was added. The absorbance was read at 565 nm with a scanning multi-well spectrophotometer. All measurements were performed in triplicate. The results were compared to control plates fixed on the day of treatment and the IC of the compound was calculated50The values are shown in table 1 below:
IC of the Compounds of Table 150Value of
Figure RE-601264DEST_PATH_IMAGE003

Claims (12)

1. A tumor-targeted polypeptide drug conjugate, which is characterized by comprising the following parts:
(1) a tumor targeting polypeptide moiety;
(2) a connector portion;
(3) a cytotoxic antitumor drug.
The tumor targeting polypeptide part can specifically recognize tumor blood vessels or tumor related receptors so as to realize the tumor targeting of the tumor targeting polypeptide part.
2. The tumor targeting peptide of claim 1, wherein the amino acid sequence is WNPLLLTRLLPA, or a polypeptide sequence or polypeptide derivative with 1-3 amino acids substituted, deleted or inserted.
3. The connector part of claim 1 is a non-cleavage connector, wherein a non-cyclic chain formed by covalent bonding between carbon atoms is used as a carbon skeleton, and the structure is as follows:
Figure RE-350286DEST_PATH_IMAGE001
；
wherein n = 4-6, specifically, the invention uses 6-aminocaproic acid as a connecting reagent to form a connector part.
4. The cytotoxic antitumor agent as claimed in claim 1, wherein nitrogen mustard, chlorambucil, adriamycin, taxol, cisplatin or the like is selected.
5. The tumor targeting polypeptide drug conjugate of claim 1, wherein the structural formula is:
Figure RE-86161DEST_PATH_IMAGE002
the tumor targeted polypeptide drug conjugate has a targeting effect on tumor cells, and can effectively kill the tumor cells.
6. The method for preparing a tumor targeting polypeptide drug conjugate (PDC-WA 1) according to claim 5, comprising the steps of:
step 1, adopting Fmoc solid phase synthesis strategy to mix Fmoc-Ala-Wang resin with Fmoc-Pro-OH, Fmoc-Leu-OH and Fmoc-Arg (R)1)-OH 、Fmoc-Thr(tBu)-OH、Fmoc-Asn(R1)-OH、Fmoc-Trp(R1) -OH is connected according to the amino acid sequence of the tumor targeting peptide WA 1;
and 2, removing the Fmoc protecting group at the N end of the tumor targeting peptide, and connecting the tumor targeting peptide with Fmoc-Acp-OH to obtain WA 1-linker-Fmoc bonded on the resin.
And 3, removing an Fmoc protecting group from the obtained WA 1-linker-Fmoc, and connecting the obtained WA 1-linker-Fmoc with chlorambucil through a chemical reaction.
Step 4, cutting PDC-WA1 from the resin by using a cracking reagent, and precipitating by using anhydrous ether; separating and purifying by preparative HPLC, and lyophilizing to obtain the final product.
7. The method of claim 6, wherein: Fmoc-Ala-Wang resin (bonding amount is 0.237 mmol/g), and reagents for removing Fmoc are Pip and DMF in a volume ratio (Pip: DMF = 1: 10-1: 1). The polypeptide coupling agent is DIC/HOAt, and the condensation reaction temperature is maintained at 0-30 ℃.
8. The method of claim 6, wherein Fmoc-Arg (R) is present1)-OH 、Fmoc-Asn(R1)-OH、Fmoc-Trp(R1) R of-OH1H, Trt, tBu, Boc, Pbf, etc.
9. The method of claim 6, wherein the Fmoc-WA1-Wang resin is subjected to Fmoc protecting group removal, and then reacted with 1 to 5-fold molar amount of DIC, HOAt and Fmoc-Acp-OH. The reaction is required to be carried out in an ultrasonic reactor, a microwave reactor and a polypeptide synthesizer reactor.
10. The method according to claim 6, wherein the Fmoc-linker-WA1-Wang resin is subjected to Fmoc protecting group removal, and then mixed with 1-5 times molar amount of DIC, HOAt and chlorambucil in an ultrasonic reactor, a microwave reactor or a polypeptide synthesizer reactor.
11. The tumor-targeting polypeptide drug conjugate (PDC-WA 1) according to claim 5, wherein the use for treating tumors comprises breast cancer, ovarian cancer, liver cancer, prostate cancer, lymphoma, melanoma, and the like.
12. The tumor-targeted polypeptide drug conjugate of claim 5, wherein the pharmaceutical preparation with the tumor-targeted polypeptide drug conjugate (PDC-WA 1) as an active ingredient comprises lyophilized powder for injection, tablet, liposome, nano-preparation, etc.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114213546A (en) * 2021-12-03 2022-03-22 华中科技大学同济医学院附属协和医院 Cleavage peptide conjugate of targeting VEGFR and application thereof
CN114380886A (en) * 2022-01-26 2022-04-22 深圳深创生物药业有限公司 Tumor targeting polypeptide, polypeptide conjugate drug and application thereof
CN114478707A (en) * 2022-03-08 2022-05-13 上海中医药大学 Conformation-locked melittin derivative, conjugate, preparation and application thereof
CN114533893A (en) * 2022-02-25 2022-05-27 天津医科大学总医院 Preparation method of polypeptide-conjugated paclitaxel with anti-glioma activity

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100279918A1 (en) * 2006-03-20 2010-11-04 Burnham Institute For Medical Research Chimeric Constructs Between Cancer-Homing Peptides and Cell-Penetrating Peptides Coupled to Anticancer Drugs and/or Diagnostic Agent/Agents
CN103304638A (en) * 2013-07-08 2013-09-18 郑州大学 PD-L1 affinity peptide with anti-tumour activity and application for same
CN107281476A (en) * 2017-04-06 2017-10-24 中国医科大学 A kind of Antigenic Peptide RL adjuvants CpGODN7909 conjugates and its preparation method and application
CN108026123A (en) * 2015-06-15 2018-05-11 杭州多禧生物科技有限公司 Hydrophilic chain junctor for coupling
CN108341854A (en) * 2018-02-09 2018-07-31 中国医科大学 A kind of novel polypeptide of cancer target and application thereof
US20180228907A1 (en) * 2014-04-14 2018-08-16 Arvinas, Inc. Cereblon ligands and bifunctional compounds comprising the same

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100279918A1 (en) * 2006-03-20 2010-11-04 Burnham Institute For Medical Research Chimeric Constructs Between Cancer-Homing Peptides and Cell-Penetrating Peptides Coupled to Anticancer Drugs and/or Diagnostic Agent/Agents
CN103304638A (en) * 2013-07-08 2013-09-18 郑州大学 PD-L1 affinity peptide with anti-tumour activity and application for same
US20180228907A1 (en) * 2014-04-14 2018-08-16 Arvinas, Inc. Cereblon ligands and bifunctional compounds comprising the same
CN108026123A (en) * 2015-06-15 2018-05-11 杭州多禧生物科技有限公司 Hydrophilic chain junctor for coupling
CN107281476A (en) * 2017-04-06 2017-10-24 中国医科大学 A kind of Antigenic Peptide RL adjuvants CpGODN7909 conjugates and its preparation method and application
CN108341854A (en) * 2018-02-09 2018-07-31 中国医科大学 A kind of novel polypeptide of cancer target and application thereof

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CAROLINE DESCÔTEAUX，等: "Design of novel tyrosine-nitrogen mustard hybrid molecules active against uterine, ovarian and breast cancer cell lines", STEROIDS, vol. 77, no. 5, pages 403 - 412 *
CHEN FU，等: "Peptideedrug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope?", ACTA PHARMACEUTICA SINICA B, vol. 13, no. 2, pages 498 - 516 *
GARY GELLERMAN，等: "Drug resistance to chlorambucil in murine B-cell leukemic cells is overcome by its conjugation to a targeting peptide", ANTI-CANCER DRUGS, vol. 24, no. 2, pages 112 - 119 *
刘巾玮，等: "肿瘤靶向肽偶联药物的研究进展", 中国新药与临床杂志, vol. 39, no. 3, pages 129 - 134 *
朱文军: "氮芥-多肽偶联物的固相合成、理化性质及抗肿瘤 活性的研究", 万方数据, pages 1 - 49 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114213546A (en) * 2021-12-03 2022-03-22 华中科技大学同济医学院附属协和医院 Cleavage peptide conjugate of targeting VEGFR and application thereof
CN114380886A (en) * 2022-01-26 2022-04-22 深圳深创生物药业有限公司 Tumor targeting polypeptide, polypeptide conjugate drug and application thereof
CN114380886B (en) * 2022-01-26 2022-10-21 深圳深创生物药业有限公司 Tumor targeting polypeptide, polypeptide conjugate drug and application thereof
CN114533893A (en) * 2022-02-25 2022-05-27 天津医科大学总医院 Preparation method of polypeptide-conjugated paclitaxel with anti-glioma activity
CN114478707A (en) * 2022-03-08 2022-05-13 上海中医药大学 Conformation-locked melittin derivative, conjugate, preparation and application thereof
CN114478707B (en) * 2022-03-08 2024-03-29 上海中医药大学 Conformational locking melittin derivative, conjugate, preparation and application thereof

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