CN104622874B - Application of the CCR4 antagonists in cancer growth and transfer is suppressed - Google Patents
Application of the CCR4 antagonists in cancer growth and transfer is suppressed Download PDFInfo
- Publication number
- CN104622874B CN104622874B CN201510081298.8A CN201510081298A CN104622874B CN 104622874 B CN104622874 B CN 104622874B CN 201510081298 A CN201510081298 A CN 201510081298A CN 104622874 B CN104622874 B CN 104622874B
- Authority
- CN
- China
- Prior art keywords
- transfer
- cancer
- ccr4
- liver cancer
- ccr4 antagonists
- 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.)
- Active
Links
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 title claims abstract description 27
- 239000005557 antagonist Substances 0.000 title claims abstract description 18
- 230000005907 cancer growth Effects 0.000 title claims abstract description 13
- 102100032976 CCR4-NOT transcription complex subunit 6 Human genes 0.000 title claims abstract 6
- 238000012546 transfer Methods 0.000 title abstract description 22
- 201000007270 liver cancer Diseases 0.000 claims abstract description 29
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 201000011510 cancer Diseases 0.000 claims abstract description 15
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims description 5
- 206010027476 Metastases Diseases 0.000 claims description 4
- 230000009401 metastasis Effects 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims 1
- 150000003384 small molecules Chemical class 0.000 claims 1
- 230000001629 suppression Effects 0.000 claims 1
- 102100037853 C-C chemokine receptor type 4 Human genes 0.000 description 25
- 210000004027 cell Anatomy 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 6
- 102100023698 C-C motif chemokine 17 Human genes 0.000 description 4
- 101000738584 Homo sapiens C-C chemokine receptor type 4 Proteins 0.000 description 4
- 101000978362 Homo sapiens C-C motif chemokine 17 Proteins 0.000 description 4
- 108060001084 Luciferase Proteins 0.000 description 4
- 239000005089 Luciferase Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000007928 intraperitoneal injection Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 210000003289 regulatory T cell Anatomy 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 102100036845 C-C motif chemokine 22 Human genes 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 210000005161 hepatic lobe Anatomy 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 102000018202 CC chemokine receptor 4 Human genes 0.000 description 2
- 108010017317 CCR4 Receptors Proteins 0.000 description 2
- 108010082169 Chemokine CCL17 Proteins 0.000 description 2
- 102000003826 Chemokine CCL17 Human genes 0.000 description 2
- 108700008625 Reporter Genes Proteins 0.000 description 2
- -1 Thiazolidine ketone Chemical class 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 230000003399 chemotactic effect Effects 0.000 description 2
- 239000005482 chemotactic factor Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 108091008927 CC chemokine receptors Proteins 0.000 description 1
- 102000005674 CCR Receptors Human genes 0.000 description 1
- 108010083701 Chemokine CCL22 Proteins 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 210000004241 Th2 cell Anatomy 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000004421 aryl sulphonamide group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000012632 fluorescent imaging Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 210000005096 hematological system Anatomy 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000011242 molecular targeted therapy Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- XELRMPRLCPFTBH-UHFFFAOYSA-N quinazoline-2,4-diamine Chemical class C1=CC=CC2=NC(N)=NC(N)=C21 XELRMPRLCPFTBH-UHFFFAOYSA-N 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to application of the CCR4 antagonists in cancer growth and transfer is suppressed, belong to biomedicine technical field, and in particular to the application of CCR4 antagonists, especially C 021 and ST45177901 in cancer especially liver cancer growth and transfer is suppressed.Compound provided by the invention has good potential applicability in clinical practice in cancer especially liver cancer growth and transfer is suppressed.
Description
Technical field
The present invention relates to biomedicine technical field, and in particular to CCR4 antagonists answering in cancer growth and transfer is suppressed
With.
Background technology
Liver cancer is clinically one of most common malignant tumour, has the characteristics of grade of malignancy is high, progress is fast, poor prognosis, sternly
Human health and life security are threaten again.China is global onset of liver cancer rate highest and several most countries that die of illness, liver cancer are suffered from
Person accounts for the 55% of the whole world.In recent years, the incidence of disease of the liver cancer in the whole world is all in rising trend, and the newly-increased cases of cancer of China is in
The new cases and death toll of No. 1 in the world, wherein liver cancer occupy first place in the world.Because there is liver abundant blood flow to supply
Should, therefore, blood vessel transfer is most important hepatoma Metastasis approach.It has been reported that more than 90% cancer patient dies from metastasis of cancer.
Domestic and international application is seldom in the active drug for the treatment of liver cancer blood vessel transfer at present, therefore, carries out the medicine of liver cancer blood vessel transfer in a deep going way
Thing study on prevention is significant.
CC-chemokine receptor 4 (CC chemokine receptor 4, CCR4) be also known as CKR4, CMKBR4, ChemR13,
K5-5 etc., belong to CC-chemokine receptor family, containing 360 amino acid residues, be positioned at No. 3 chromosome p24-p21.3 regions,
For 7 transmembrane G protein coupled receptors, each lymphocyte and tissue, CCR4 high expression and a variety of hematological systems are mainly expressed in
Infiltration, the transfer of tumour and malignant solid tumor are related to prognosis.Known CCR4 high-affinity parts have two, respectively chest
Gland CCL17 (Thymus and activation regulated chemokine, TARC/CCL17) and huge
Phagocyte derives chemotactic factor (CF) (macrophage-derivedchemokine, MDC/CCL22).CCR4 mainly passes through CCR4+
Treg cells and CCR4+Th2 cells play immunological effects, if the CCR4 of Treg cell surfaces is by with its part TARC, MDC
With reference to chemotactic Treg cells, cause immunologic escape, so as to cause bad clinical consequences.Suppressed by studying CCR4 antagonists
TARC/MDC-CCR4 signal paths, it is possible to as the new strategy of malignant tumour molecular targeted therapy.
CCR4 antagonists can be divided into according to its chemical constitution：Thiazolidine ketone, lactams, thiazolamine class, aryl
Sulfonamides, phenodiazine yl pyrimidines class, 2,4- diamino quinazolines and cyclic amine compound etc..In asthma, rhinitis, dermatitis, blood
There is good therapeutic effect in the research of the diseases such as bolt disease, autoimmune disease, there is larger clinical practice valency
Value.
So far, there is not yet CCR4 antagonists are used to treat liver cancer growth and the report of transfer.
The content of the invention
Present invention research finds that CCR4 antagonists, especially micromolecular compound c-021 and ST45177901 can be effectively short of money
Anti- CCR4, have the function that to suppress cancer especially liver cancer growth and transfer.
The micromolecular compound c-021 and ST45177901 is CCR4 antagonists, passes through mouse original position liver cancer model
Research finds that both compounds can be by effective antagonism CCR4, so as to suppress TARC/MDC-CCR4 signal path chemotactics
Treg cells, the growth and transfer of liver cancer in Mice Body are effectively inhibited, there is good potential applicability in clinical practice.
Therefore, the present invention relates to the following：
1.CCR4 antagonists are preparing the purposes in being used to suppress cancer growth and suppress the medicine of cancer metastasis.
2. according to the purposes described in the 1st, the CCR4 antagonists be micromolecular compound c-021, ST45177901 or
It is combined, and described micromolecular compound c-021, ST45177901 structural formula are respectively
With
3. according to the purposes described in the 1st or 2, the cancer is liver cancer.
4. according to the purposes described in the 1st or 2, the CCR4 antagonists can be prepared to injection, tablet or capsule
Agent.
The present invention shows that CCR4 antagonists are especially small using the compliance test result result of rat liver cancer orthotopic transplantation experiment
Molecular compound c-021 and ST45177901, it can effectively suppress the growth and transfer of tumour cell, c-021 depression effect
It is more notable.
Micromolecular compound provided by the invention has good potential applicability in clinical practice in treatment liver cancer growth and transfer.
Brief description of the drawings
The effect that Fig. 1 compounds c-021 grow and shifted to rat liver cancer
The effect that Fig. 2 compounds ST45177901 grow and shifted to rat liver cancer
Embodiment
Embodiment 1：Compound
1. micromolecular compound c-021 is purchased from Tocris companies (article No.：3581, purity>99%), the compound molecule formula
For C27H41N5O22HCl, structure are as follows：
2. micromolecular compound ST45177901 is purchased from Timtec companies (article No.：MFCD04147999, purity>99%),
The compound molecule formula is C26H16ClN3O4S3, structure is as follows：
Embodiment 2：CCR4 antagonists are used for the zoopery for treating liver cancer growth and transfer
Orthotopic transplantation tumor model of hepatocellular carcinoma in mice can effectively simulate the process that liver cancer grows, attacks and shifted naturally, be research liver
Conventional animal experimental model (Gao YS, Chen XP, Li KY, the Wu ZD.Nude mice model of human of cancer
hepatocellular carcinoma via orthotopic implantati on of histologically
intact tissue.World JGastroenterol.2004.10:3107-3111).Therefore compound c-021 is verified with it
And effects of the ST45177901 in liver cancer growth and transfer.
1st, animal
C57/6BL mouse, male, 20~24g of body weight, every group of 6/cage group support, are divided into 4 groups.It is purchased from Beijing dimension tonneau China
Experimental animal Technology Co., Ltd., raise in SPF level Animal Houses.
2nd, cell
Using the luciferase assay of IVIS companies, the Hepa1-6 cells containing luciferase reporter gene are constructed
System.And give every mouse inoculation 3*106Individual above-mentioned cell, obtain experiment mice.
The specific construction method of the Hepa1-6 cell lines containing luciferase reporter gene is as follows：
Hepa1-6 cells are purchased from ATCC cell bank (article No.s：CRL-1830), luciferase reporting plasmid is purchased from IVIS companies
(pcDNA6-Luci).Will be per plasmid described in 2ug and 200ul jetPRIME buffer (companies：Polyplus, article No.：PT-
114-07) mix, then add 4ul jetPRIME transfection reagents (company：Polyplus, article No.：PT-114-07) transfect extremely
Hepa1-6 cells, 2mg/mL G418 (companies are added after cultivating 48h：Amresco, article No. E859-5G) continue to cultivate, continuous training
Support 2 weeks, acquisition surely turns cell line.
3rd, medicine
Experiment mice is grouped：
C-021 groups：
Experimental group：Every two days intraperitoneal injection micromolecular compounds c-021,10 μm of ol/kg
Control group：Every two days intraperitoneal injection PBS
ST45177901 groups：
Experimental group：Every two days intraperitoneal injection micromolecular compounds ST45177901,10 μm of ol/kg
Control group：Every two days intraperitoneal injection PBS
4th, laboratory apparatus
Instrument title：Small animal living body in-vivo imaging system IVIS Spectrum, model：IVIS Spectrum, are produced
Producer：U.S. Caliper.
5th, experimental method
Mouse is noted with 10% chloraldurate (being purchased from Chemical Reagent Co., Ltd., Sinopharm Group, article No. 30037517) abdominal cavity
Anesthesia is penetrated, dorsal position is fixed, the sterilization of 75% alcohol wipe belly, cuts off superfluous hairs, exposure skin of abdomen, along ventrimeson in sword
0.5cm osculums are cut off under prominent, exposure liver, extrude left lobe of liver, fix left lobe of liver with ophthalmic tweezers, injection 20-30 μ l contain 3*106Institute
State the Hepa1-6 containing luciferase and surely turn cell in liver parenchyma, light tabletting, which is carved, sends left lobe of liver back to abdominal cavity, sutures muscle respectively
Layer and skin.Respectively compound c-021 (10 μm of ol/kg) and ST45177901 (10 μm of ol/ is injected intraperitoneally in every two days in experimental group
Kg), PBS is then injected intraperitoneally in control group.1d, 14d (for c-021)/10d (for ST45177901) are carried out respectively after surgery
Fluorescent imaging, observe liver cancer cell growth and transfer case.
(1) influence that compound c-021 grows and shifted to rat liver cancer
Post operation 1d detects two groups of fluorescence signal intensities and has no significant difference, 14d is handled by administration, through c-021 processing
Experimental mice liver cancer cells fluorescence signal be nearly no detectable, the significant difference compared with control group, and glimmering in control group
Optical signal skewness, there are multiple strong signaling points, be transfer stove signal (Fig. 1).From above-mentioned experimental result, c-021 tools
Play the role of significantly to suppress liver cancer cell growth and transfer.
(2) influence that compound ST45177901 grows and shifted to rat liver cancer
Post operation 1d detects two groups of fluorescence signal intensities and has no significant difference, 10d is handled by administration, through ST45177901
The experimental mice liver cancer cells fluorescence signal of processing is markedly less than control group, wherein three are nearly no detectable fluorescence signal,
And fluorescence signal skewness in control group, there are multiple strong signaling points, be transfer stove signal (Fig. 2).By above-mentioned experimental result
Understand, ST45177901 has the function that significantly to suppress liver cancer cell growth and transfer.
Claims (2)
1.CCR4 antagonists are as sole active agent in the medicine for being used for suppressing cancer growth and suppression cancer metastasis is prepared
Purposes, wherein the cancer is liver cancer, the CCR4 antagonists are micromolecular compound ST45177901, the small molecule chemical combination
Thing ST45177901 structural formula is
2. purposes according to claim 1, wherein the CCR4 antagonists can be prepared to injection, tablet or capsule
Agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510081298.8A CN104622874B (en) | 2015-02-15 | 2015-02-15 | Application of the CCR4 antagonists in cancer growth and transfer is suppressed |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510081298.8A CN104622874B (en) | 2015-02-15 | 2015-02-15 | Application of the CCR4 antagonists in cancer growth and transfer is suppressed |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104622874A CN104622874A (en) | 2015-05-20 |
| CN104622874B true CN104622874B (en) | 2017-12-26 |
Family
ID=53202438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510081298.8A Active CN104622874B (en) | 2015-02-15 | 2015-02-15 | Application of the CCR4 antagonists in cancer growth and transfer is suppressed |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104622874B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018211936A1 (en) * | 2017-05-19 | 2018-11-22 | 真吾 前田 | Method for inhibiting regulatory t cell infiltration using ccr4 inhibition and method for treating canine neoplastic disease |
| CN114957238B (en) * | 2022-06-23 | 2024-02-06 | 南京工业大学 | 3-hydroxy-pyrrole-2-ketone compound containing 1,3, 4-thiadiazole and synthetic method and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0810869D0 (en) * | 2008-06-13 | 2008-07-23 | Isis Innovation | Vaccine adjuvant composition |
| WO2013082429A1 (en) * | 2011-12-01 | 2013-06-06 | Chemocentryx, Inc. | Substituted benzimidazoles and benzopyrazoles as ccr(4) antagonists |
| WO2013140148A1 (en) * | 2012-03-19 | 2013-09-26 | Imperial Innovations Limited | Quinazoline compounds and their use in therapy |
-
2015
- 2015-02-15 CN CN201510081298.8A patent/CN104622874B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN104622874A (en) | 2015-05-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101589026B (en) | Method of treatment of glioma brain tumour | |
| CN102105151A (en) | Use of a CDK inhibitor for the treatment of glioma | |
| CN108697661A (en) | Combination for treating cancer | |
| EP3023104B1 (en) | Recombinant ganoderma lucidum immunomodulatory protein (rlz-8) for use in treating melanoma | |
| CN109761899A (en) | Quinoline, its pharmaceutically acceptable salt or its solvate, its application, drug and pharmaceutical composition | |
| CN104622874B (en) | Application of the CCR4 antagonists in cancer growth and transfer is suppressed | |
| CN106794180A (en) | Conjoint therapy | |
| KR102508303B1 (en) | Novel uses of pure 5-HT6 receptor antagonists | |
| CN101429201A (en) | Lemon acid berbamine salt, preparation method and application thereof | |
| CN109715191A (en) | Pharmaceutical associations for the conversion of neoplastic cells into non-neoplastic cells and uses thereof | |
| CN109715190A (en) | Pharmaceutical associations of growth factor receptor agonists and adhesion protein inhibitors for converting neoplastic cells to non-neoplastic cells and uses thereof | |
| CN101679499B (en) | Anti-tumor drug, medicament, composition, and use thereof | |
| US9345704B2 (en) | Materials and methods for suppressing and/or treating neurofibroma and related tumors | |
| CN102813914B (en) | Medicinal composition used for treating or preventing cerebrovascular disease and related diseases | |
| CN107596371A (en) | The application of P2Y1 acceptors and its blocking agent in prevention and treatment depression and/or antianxiety disease | |
| CN106421796B (en) | Sorafenib combines CCR4 antagonist and is inhibiting the application in cancer growth and transfer | |
| CN111635754A (en) | Application of benzothioanthracene derivatives | |
| CN105497900A (en) | Drug-resistant target for resisting undifferentiated thyroid cancer and application thereof | |
| WO2022143984A1 (en) | Pharmaceutical composition for treating cancer, preparation method therefor and use thereof | |
| CN110075131A (en) | Application of the zika virus attenuated strain in treatment glioma | |
| CN115444927B (en) | Application of Ai Mode S in preparation of medicine for treating triple negative breast cancer | |
| CN102719436A (en) | Oligonucleotides and usage thereof in preparation of medicine for preventing and curing myocardial hypertrophy and heart failure | |
| CN113350488B (en) | Application of oral hypoglycemic peptide OHP in preparation of medicine for resisting neurodegenerative diseases | |
| CN108721621A (en) | Inhibit micromolecular compound and the application of liver fibrosis | |
| CN107303290A (en) | The new application of aromatic rings allylamine compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant |