CN106421796B - Sorafenib combines CCR4 antagonist and is inhibiting the application in cancer growth and transfer - Google Patents
Sorafenib combines CCR4 antagonist and is inhibiting the application in cancer growth and transfer Download PDFInfo
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- 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
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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Abstract
The present invention relates to Sorafenib joint CCR4 antagonists to inhibit the application in cancer growth and transfer, belong to biomedicine technical field, inhibiting the application in the tumour growths such as cancer such as liver cancer, kidney, lung cancer, breast cancer, melanoma, thyroid cancer, prostate cancer and transfer more particularly to Sorafenib drug and CCR4 antagonist, especially C-021 and ST45177901 combination therapy.Compound combination therapy provided by the invention has good potential applicability in clinical practice in inhibiting the tumour growths such as cancer especially liver cancer, kidney, lung cancer, breast cancer, melanoma, thyroid cancer, prostate cancer and transfer.
Description
Technical field
The present invention relates to biomedicine technical fields, and in particular to Sorafenib is inhibiting with CCR4 antagonist combination therapy
Application in cancer growth and transfer.
Background technique
Sorafenib (sorafenib) is a kind of oral multi-kinase inhibitor, can effectively inhibit tumor cell proliferation
It is generated with new vessels, it is significant to liver cancer, the therapeutic effect of kidney, in non-small cell lung cancer, melanoma, thyroid cancer, cream
It is also had been reported that in the Therapy study of the cancers such as gland cancer, prostate cancer.
Liver cancer is clinically one of most common malignant tumour, has the characteristics that grade of malignancy is high, progress is fast, poor prognosis, sternly
Threaten human health and life security again.China is global onset of liver cancer rate highest and several most countries that die of illness, and liver cancer is suffered from
Person accounts for about the 55% of the whole world.In recent years, disease incidence of the liver cancer in the whole world is all in rising trend, and the newly-increased cases of cancer of China is in
No. 1 in the world, wherein the new cases of liver cancer and death toll occupy first place in the world.Since liver is supplied with blood flow abundant
It answers, therefore, blood vessel transfer is most important hepatoma Metastasis approach.It has been reported that 90% or more cancer patient dies of 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
Object study on prevention is of great significance.
Sorafenib is that first of FDA approval is also currently the only one line targeting medicine for treating advanced liver cancer
Object.SHARP studies have shown that Sorafenib treatment group can effectively extend compared to the control group total life span (OS, 10.7 months
Vs7.9 months, P < 0.001) and disease developing time (TTP, vs2.8 months 5.5 months, P < 0.001).But as clinic is controlled
The problem for the treatment of is goed deep into research, Sorafenib drug resistance becomes especially prominent.It has been reported that Sorafenib is for the HBV positive
The response rate of liver cancer is extremely low, and most of clinical patients will appear Sorafenib resistance after taking Sorafenib 3-6 months
Effect, but the resistance mechanism about Sorafenib is still not clear at present.
CC-chemokine receptor 4 (CC chemokine receptor 4, CCR4) be also known as CKR4, CMKBR4, ChemR13,
K5-5 etc. belongs to CC-chemokine receptor family, contains 360 amino acid residues, is positioned at No. 3 regions chromosome p24-p21.3,
For 7 transmembrane G protein coupled receptors, it is mainly expressed in each lymphocyte and tissue, high expression and a variety of hematological systems of CCR4
Infiltration, the transfer of tumour and malignant solid tumor are related to prognosis.There are two known CCR4 high-affinity parts, respectively chest
Gland activated regulatory chemokine (Thymus and activation regulated chemokine, TARC/CCL17) and huge
Phagocyte is derivative chemotactic factor (CF) (macrophage-derived chemokine, MDC/CCL22).CCR4 mainly passes through modulability
T cell (Treg) play immunological effect, as Treg cell surface CCR4 by and its ligand CCL22/CCL17 combination chemotactic
Treg cell, causes immunologic escape, so as to cause bad clinical consequences.
CCR4 antagonist can be divided into according to its chemical structure: 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 biggish clinical application valence
Value.
So far, there is not yet Sorafenib and CCR4 antagonist combination are for treating liver cancer, kidney, non-small cell lung
The tumour growths such as cancer, melanoma, thyroid cancer, breast cancer, prostate cancer and the report of transfer.
Summary of the invention
For the present inventor the study found that Sorafenib can stimulate tumour cell hypersecretion CCL22 and CCL17, chemotactic Treg is thin
Born of the same parents' infiltration causes Sorafenib to treat drug resistance.Using Sorafenib and CCR4 antagonist, especially small molecule compound C-021 or
CCL22/CCL17-CCR4 signal path chemotactic Treg cell can be effectively suppressed, to significantly press down in ST45177901 combination therapy
The growth and transfer of tumour cell processed.
Sorafenib provided by the invention and CCR4 antagonist combination therapy scheme are in treatment liver cancer, kidney, lung cancer, mammary gland
There is good potential applicability in clinical practice in the tumour growths such as cancer, melanoma, thyroid cancer, prostate cancer and transfer.
Therefore, the present invention relates to the following termss:
1. a kind of pharmaceutical composition, it includes Sorafenibs and CCR4 antagonist.
2. the pharmaceutical composition according to 1, wherein the CCR4 antagonist includes can be excellent with the compound of antagonism CCR4
Choosing is selected from following kind of compound: thiazolidine ketone, lactams, thiazolamine class, arylsulfonamides, phenodiazine base are phonetic
Pyridine class, 2,4- diamino quinazolines and cyclic amine compound.
3. the pharmaceutical composition according to 1, wherein the CCR4 antagonist is selected from small molecule compound C-021, small point
Sub- compound ST45177901, its analogue or any combination thereof,
The wherein structural formula of the small molecule compound C-021 are as follows:
The small molecule compound ST45177901 structural formula are as follows:
4. Sorafenib is used to combine the purposes for preparing drug with CCR4 antagonist, the drug is used for treating cancer.
5. the purposes according to 4, the treatment includes inhibiting cancer growth and inhibition cancer metastasis.
6. the purposes according to 4, wherein the CCR4 antagonist includes that can be preferably selected from the compound of antagonism CCR4
Following kind of compound: thiazolidine ketone, lactams, thiazolamine class, arylsulfonamides, phenodiazine yl pyrimidines class,
2,4- diamino quinazolines and cyclic amine compound.
7. the purposes according to 4, wherein the CCR4 antagonist is selected from small molecule compound C-021, small molecule chemical combination
Object ST45177901, its analogue or any combination thereof,
The wherein structural formula of the small molecule compound C-021 are as follows:
The small molecule compound ST45177901 structural formula are as follows:
8. the purposes according to 4, wherein the cancer is selected from liver cancer, kidney, lung cancer, breast cancer, melanoma, first shape
Gland cancer, prostate cancer.
9. the pharmaceutical composition according to 1, wherein the CCR4 antagonist is separately or simultaneously applied with Sorafenib.
10. the pharmaceutical composition according to 1, wherein the CCR4 antagonist is injection, tablet or capsule.
Detailed description of the invention
Fig. 1 Sorafenib handles liver cancer cell lines chemotactic factor (CF), cell factor variation detection
Fig. 2 Sorafenib and CCR4 antagonist combination therapy effect detection
Specific embodiment
Embodiment 1: compound
1. Sorafenib bulk pharmaceutical chemicals are purchased from Yao Du company.
2. small molecule compound c-021 is purchased from Tocris company (article No.: 3581, purity > 99%), the compound molecule
Formula is C27H41N5O22HCl, structure are as follows:
3. small molecule compound ST45177901 is purchased from Timtec company (article No.: MFCD04147999, purity > 99%),
The compound molecule formula is C26H16ClN3O4S3, structure is as follows:
Embodiment 2: Sorafenib handles liver cancer cell lines chemotactic factor (CF), cell factor variation detection
Real-time fluorescence quantitative PCR detection through various concentration Sorafenib stimulate liver cancer cell lines after chemotactic factor (CF), cell because
The variation of the secretion levels such as son filters out the hypersecretion factor that Sorafenib induction generates.
1, cell
Murine hepatocarcinoma cell system Hepa1-6 cell is purchased from ATCC cell bank (article No.: CRL-1830).
2, drug
Hepa1-6 cell 48h is handled with various concentration Sorafenib:
Experimental group 1: being added 4 μM of Sorafenibs in cell culture medium, cultivates 48 hours；
Experimental group 2: being added 2 μM of Sorafenibs in cell culture medium, cultivates 48 hours；
Control group: being added isometric DMSO, cultivates 48h.
3, laboratory apparatus
Instrument title: ViiATM7 fluorescence quantitative PCR instruments, model: ViiATM7, produce producer: American AB I.
4, experimental method
It will be separately added into 2 μM, 4 μM of Sorafenibs or DMSO in cell culture medium, after cultivating 48h, extract cell RNA, it is inverse
It is transcribed into cDNA, real-time PCR detects chemotactic factor (CF), cell factor variation.
The result shows that CCL22 and CCL17 expression dramatically increases (Fig. 1), table compared with control group after Sorafenib processing
The generation of bright Sorafenib drug resistance is related with CCL22/CCL17-CCR4 signal path activation, and chemotactic Treg promotes tumour immunity
Caused by escape.
Embodiment 3: Sorafenib joint CCR4 antagonist is used to treat the zoopery of liver cancer growth and transfer
The subcutaneous lotus knurl model of mouse is the model of routine observation tumour growth, transfer, thus with its verify Sorafenib with
The effect of CCR4 antagonist combination therapy liver cancer growth and transfer.
1, animal
C57BL/6 mouse (being male, 20~24g of weight, every group of 6/cage group rearing) is purchased from the experiment of Beijing dimension tonneau China
Zoo technical Co., Ltd raises in SPF grades of animal houses.6 groups are divided into be tested.
2, cell
Murine hepatocarcinoma cell system Hepa1-6 cell is purchased from ATCC cell bank (article No.: CRL-1830), every mouse inoculation 3*
106Cell obtains experiment mice.
3, drug
Experiment mice is grouped:
Experimental group 1: every two days stomach-filling Sorafenibs, 40mg/kg, while PBS is injected intraperitoneally
Experimental group 2: every two days stomach-filling Sorafenibs, 40mg/kg, while CCR4 antagonist is injected intraperitoneally (with small molecule
For closing object c-021,10 μm of ol/kg)
Experimental group 3: every two days stomach-filling Sorafenibs, 10mg/kg, while PBS is injected intraperitoneally
Experimental group 4: every two days stomach-filling Sorafenibs, 10mg/kg, while CCR4 antagonist is injected intraperitoneally (with small molecule
For closing object c-021,10 μm of ol/kg)
Experimental group 5: every two days stomach-filling PBS, while be injected intraperitoneally CCR4 antagonist (by taking small molecule compound c-021 as an example,
10μmol/kg)
Control group: every two days stomach-filling PBS, while PBS is injected intraperitoneally
4, experimental method
By C57BL/6 mouse hypodermic inoculation 3*106Hepa1-6 cell, after 7 days distinguish stomach-filling various dose Sorafenib and
CCR4 antagonist (by taking small molecule compound c-021 as an example) treatment is injected intraperitoneally, the size of every two days record tumours calculates tumour
Volume (long * wide/2 * wide) draws tumor growth curve.After 14 days, subcutaneous tumor is removed, record size is simultaneously weighed.
The result shows that the growth of tumour can be effectively suppressed in 40mg/kg Sorafenib joint CCR4 antagonist, individually give
CCR4 treatment also has certain effect, individually gives 10mg/kg Sorafenib and is more conducive to tumour growth (Fig. 2) to a certain extent.
Result similar to the above is also obtained using small molecule compound ST45177901.
These results explanation, Sorafenib stimulate tumour cell hypersecretion CCL22 and CCL17, chemotactic Treg cellular infiltration
Promote tumor immune escape, induce Sorafenib drug resistance, therefore it is unsatisfactory individually to give Sorafenib therapeutic effect.And rope is drawn
The activation of CCL22/CCL17-CCR4 signal path can be effectively suppressed in Fei Ni and CCR4 antagonist combination therapy, so that tumour be inhibited to exempt from
Epidemic disease escape, therefore the growth and transfer of tumour cell can be significantly inhibited.In treatment liver cancer, kidney, lung cancer, breast cancer, black
There is good potential applicability in clinical practice in the tumour growths such as plain tumor, thyroid cancer, prostate cancer and transfer.
Claims (9)
1. a kind of pharmaceutical composition, it includes Sorafenibs and CCR4 antagonist.
2. pharmaceutical composition according to claim 1, wherein the CCR4 antagonist includes can be with the chemical combination of antagonism CCR4
Object is selected from following kind of compound: thiazolidine ketone, lactams, thiazolamine class, arylsulfonamides, phenodiazine
Yl pyrimidines class, 2,4- diamino quinazolines and cyclic amine compound.
3. pharmaceutical composition according to claim 1, wherein the CCR4 antagonist be selected from small molecule compound C-021,
Small molecule compound ST45177901, its analogue or any combination thereof,
The wherein structural formula of the small molecule compound C-021 are as follows:
The small molecule compound ST45177901 structural formula are as follows:
4. Sorafenib is used to combine the purposes for preparing drug with CCR4 antagonist, the drug is used for treating cancer, wherein institute
It states cancer and is selected from liver cancer, kidney, lung cancer, breast cancer, melanoma, thyroid cancer, prostate cancer.
5. purposes according to claim 4, the treatment includes inhibiting cancer growth and inhibition cancer metastasis.
6. purposes according to claim 4, wherein the CCR4 antagonist includes that can be selected with the compound of antagonism CCR4
From following kind of compound: thiazolidine ketone, lactams, thiazolamine class, arylsulfonamides, phenodiazine yl pyrimidines
Class, 2,4- diamino quinazolines and cyclic amine compound.
7. purposes according to claim 4, wherein the CCR4 antagonist is selected from small molecule compound C-021, small molecule
Compound ST45177901, its analogue or any combination thereof,
The wherein structural formula of the small molecule compound C-021 are as follows:
The small molecule compound ST45177901 structural formula are as follows:
8. pharmaceutical composition according to claim 1, wherein the CCR4 antagonist is separately or simultaneously applied with Sorafenib
With.
9. pharmaceutical composition according to claim 1, wherein the CCR4 antagonist is injection, tablet or capsule.
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| CN101940569A (en) * | 2009-07-07 | 2011-01-12 | 鼎泓国际投资（香港）有限公司 | Medicament composition containing sorafenib, artemisinin and artemisinin derivative and application thereof in preparing medicament for treating cancer |
| CN103969452A (en) * | 2014-05-30 | 2014-08-06 | 中国人民解放军第二军医大学 | Classification diagnostic kit for liver cancer Sorafenib personalized treatment |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101940569A (en) * | 2009-07-07 | 2011-01-12 | 鼎泓国际投资（香港）有限公司 | Medicament composition containing sorafenib, artemisinin and artemisinin derivative and application thereof in preparing medicament for treating cancer |
| CN103969452A (en) * | 2014-05-30 | 2014-08-06 | 中国人民解放军第二军医大学 | Classification diagnostic kit for liver cancer Sorafenib personalized treatment |
Non-Patent Citations (4)
| Title |
|---|
| CCR4 mediates CCL17 (TARC)-induced migration of human colon cancer cells via RhoA/Rho-kinase signaling;A.A.Al-haidari.I.Syk.H.Thorlacius;《Int J Colorectal Dis》;20130507;第28卷;第1479-1487页 * |
| CXC Chemokine Receptor 4 is Essential for Maintenance of Renal Cell Carcinoma-Initiating Cells and Predicts Metastasis;MAXIMILIAN GASSENMAIER,et al;《STEM CELLS》;20130430;第1467-1476页 * |
| CXCR4-Targeted Lipid-Coated PLGA Nanoparticles Deliver Sorafenib and Overcome Acquired Drug Resistance in Liver Cancer;Dong-Yu Gao,et al;《Biomaterials》;20151231;第67卷;第194-203页 * |
| Tumor-Associated Neutrophils Recruit Macrophages and T-regulatory Cells to Promote Progression of Hepatocellular Carcinoma and Resistance to Sorafenib;Shao-Lai Zhou,et al;《Gastroenterology》;20160630;第150卷(第7期);第1646-1658页 * |
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