CN107349427A - Applications and antineoplastic pharmaceutical compositions of the compound L Y2228820 in antineoplastic chemotherapy medicine sensitizer is prepared - Google Patents
Applications and antineoplastic pharmaceutical compositions of the compound L Y2228820 in antineoplastic chemotherapy medicine sensitizer is prepared Download PDFInfo
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- CN107349427A CN107349427A CN201710653204.9A CN201710653204A CN107349427A CN 107349427 A CN107349427 A CN 107349427A CN 201710653204 A CN201710653204 A CN 201710653204A CN 107349427 A CN107349427 A CN 107349427A
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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Abstract
The invention discloses applications of the compound L Y2228820 in antineoplastic chemotherapy medicine sensitizer is prepared and antineoplastic pharmaceutical compositions.The antineoplastic pharmaceutical compositions, including chemotherapeutics and sensitizer, the sensitizer are compound L Y2228820.Present invention research finds that p38 kinase inhibitors Ceritinib can be used as antineoplastic chemotherapy medicine resistance sensitizer, during with chemotherapy drugs in combination medication, drug resistance caused by tumours of chemotherapeutic agents can be overcome, the effect of chemotherapeutics is to cells of resistant tumors is significantly increased, new approach and means are provided for effectively treatment tumour.
Description
Technical field
The present invention relates to medicine, and antineoplastic chemotherapy medicine increasing is being prepared more particularly to compound L Y2228820
Application and antineoplastic pharmaceutical compositions in quick dose.
Background technology
Cancer is first big " killer " of serious threat our people's life and health, it has also become publilc health urgently to be resolved hurrily
Problem！Current research prompts China's cancer new cases and death to increase year by year, wherein 2015 there are about 429.2 Wan Xinfa
Invasive cancer case, average hair about 12000 new daily；Meanwhile have within 2015 281.4 ten thousand cancer mortality cases, it is average every
Its about 7500 people dies from cancer.
The essential therapeutic arsenals of malignant tumour have operative treatment, radiation and chemotherapy etc. at present.Swollen for being diagnosed as late period
The patient of knurl and have occurred and that for the patient of transfer, chemotherapy is a preferably selection, it may be possible to helps patient to extend existence
Time and the unique selection for improving prognosis quality of life.But tumor drug resistance often results in chemotherapy failure, so as to cause disease
Feelings deteriorate even dead.Tumor drug resistance is divided into primary drug resistance and acquired resistance.Statistics shows, annual dead tumour
In patient, belong to primary drug resistance accounts for 61%, and belong to acquired resistance accounts for 33%.In a sense, more than 90%
The death of tumor patient is related to tumor drug resistance.Therefore, tumor drug resistance is that the key that successful treatment malignant tumour is badly in need of solving is asked
One of topic.
For many years, reverse of the researcher to tumor drug resistance has been carried out widely studied.Research confirms many compounds
Can effective reversing tumor resistance in vitro, mainly including calcium-ion channel antagonists (Verapamil, nicardipine, full Buddhist nun
It is flat), cyclosporine analog derivative (cyclosporin), quinoline derivatives (quinine, quinindium), flavone derivative is (flavonols, different
Flavones), estrogen modulators class (TAM, Toremifene) etc..These medicines mainly using P-gp albumen as target spot, with
MDR classes drug competition or it is noncompetitive combine P-gp, reduce P-gp and combined with chemotherapeutics, suppression drug efflux so that
Recover sensitiveness of the tumour cell to chemotherapeutics.
Compound L Y2228820 is new effective p38 Mitogen activated protein kinase (MAPK) pathway inhibitor,
Its structural formula is as shown in formula I：
Document report LY2228820 can significantly inhibit p38MAPK signals by suppressing HSP27 phosphorylations, and HSP27 is
P38MAPK downstream targets, HSP27 expressions are not influenceed.LY2228820 acts on Turnover of Mouse Peritoneal Macrophages, and it is more to suppress fat
The TNF α of sugared (LPS)-induction is formed, IC50 5.2nM.
The content of the invention
The present invention is found that a kind of compound L Y2228820 new application by research, and LY2228820 can be used as anti-swollen
The sensitizer of knurl chemotherapeutics, the killing that can effectively improve chemotherapeutics to cells of resistant tumors is shared with chemotherapeutics.
Applications of the compound L Y2228820 in antineoplastic chemotherapy medicine sensitizer is prepared.The present invention is sent out through experimental study
Existing, compound L Y2228820 can overcome drug resistance of the tumour cell to chemotherapeutics when with chemotherapy drugs in combination medication,
Significantly increase therapeutic effect of the chemotherapeutics to cells of resistant tumors.
The tumour that the present invention is applicable does not have specific characteristics, and in general tumour, sensitizer of the present invention is respectively provided with effect.
Preferably, the tumour is liver cancer, cancer of pancreas, cholangiocarcinoma, breast cancer, colon cancer, lung cancer or oophoroma.
It is further preferred that the tumour is liver cancer.
Common Chemotherapy medicine has：
Alkylating agent：Nimustine, BCNU, lomustine, endoxan, ifosfamide, glyciphosphoramide.
Antimetabolite：Deoxygenate fluorine guanosine, how western fluorine bird pyridine, 5 FU 5 fluorouracil, mercaptopurine, thioguanine, cytarabine, fluorine
Guanosine, Tegafur, gemcitabine, Carmofur, hydroxycarbamide, methotrexate (MTX), excellent fudding, ancitabine.
Antitumor antibiotics：Actinomycin D, Doxorubicin, daunorubicin, epirubicin, mitomycin, Peplomycin,
Bleomycin A5, THP.
Antitumor animals and plants component drugs：Irinotecan, harringtonine, HCPT, Vinorelbine, taxol, Thailand
Suo Di, TPT, vincristine, eldisine, Vindesine, vincaleukoblastinum, Teniposide, Etoposide, elemene
Antitumor steroids：His progesterone, tamoxifen of atamestane, Anastrozole, aminoglutethimide, Letrozole, formestane, first
It is fragrant.
Miscellany：L-Asparaginasum, carboplatin, cis-platinum, Dacarbazine, oxaliplatin, OXA, can platinum sand difficult to understand, mitoxantrone,
Procarbazine.
Preferably, the chemotherapeutics is taxol, Docetaxel, vinorelbine, vincristine or adriamycin.
Present invention also offers a kind of antineoplastic pharmaceutical compositions, including chemotherapeutics and sensitizer, the sensitizer is
Compound L Y2228820.
Antineoplastic pharmaceutical compositions of the present invention are not had specific characteristics to the type of tumour, and in general tumour can be applicable.It is excellent
Choosing, the tumour is liver cancer, cancer of pancreas, cholangiocarcinoma, breast cancer, colon cancer, lung cancer or oophoroma.
It is further preferred that the tumour is liver cancer.
Preferably, the tumour produces drug resistance to the chemotherapeutics.
Specificity, conventional chemotherapeutics are not applicable chemotherapeutics yet in antineoplastic pharmaceutical compositions of the present invention,
Conventional chemotherapeutics species has hereinbefore been described.Preferably, the chemotherapeutics is taxol, Docetaxel, length
Spring Rui Bin, vincristine or adriamycin.
Present invention research finds that p38 kinase inhibitors Ceritinib can be used as antineoplastic chemotherapy medicine resistance sensitizer,
During with chemotherapy drugs in combination medication, drug resistance caused by tumours of chemotherapeutic agents can be overcome, significantly increase chemotherapeutics to resistance to
The effect of medicine tumour cell, new approach and means are provided for effectively treatment tumour.
Brief description of the drawings
Fig. 1 is that LY2228820 influences result figure to SK-hep-1 and SK-cbt-2 cells survivals rate.
Fig. 2 is that Docetaxel is used alone and shared with LY2228820 on SK-cbt-2 cells survivals rate influence result
Figure.
Fig. 3 is that taxol is used alone and shared with LY2228820 on SK-cbt-2 cells survivals rate influence result figure.
Fig. 4 is that vinorelbine is used alone and shared with LY2228820 on SK-cbt-2 cells survivals rate influence result figure.
Fig. 5 is that adriamycin is used alone and shared with LY2228820 on SK-cbt-2 cells survivals rate influence result figure.
Embodiment
Cell line：Liver cancer drug-resistant cell strain SK-cbt-2 and its parental cell SK-hep-1.
Reagent consumptive material：MEM nutrient solutions (Hangzhou Ji promise), 0.25% pancreatin (Hangzhou Ji promise), hyclone (Hyclone),
100mm culture dishes (Corning), 96 orifice plates (BD), MTT (sigma), DMSO (Shanghai traditional Chinese medicines), taxol (Suo Laibao) are more western
Taxol (Suo Laibao), vinorelbine (Dalian U.S. logical sequence), adriamycin (Dalian U.S. logical sequence), LY2228820 (Selleck).
Instrument：Cell culture incubator, superclean bench, ELIASA.
Embodiment 1
Chemotherapeutics is to drug-resistant cell strain SK-cbt-2 and its parental generation SK-hep-1 lethal effects.
(1) experimental method
SK-cbt-2 is inoculated in 100mm culture dishes, cultivates 72 hours, removes nutrient solution；0.25% pancreatin digests, and collects thin
Born of the same parents, cell count, the single cell suspension of 20000/ml concentration is prepared, is inoculated with 0.2ml single cell suspensions per hole respectively to 96 holes
Plate, it is 4000 per hole total cell number；Overnight incubation, it is separately added into corresponding chemotherapeutics processing；The processing of Docetaxel
Concentration be 0,0.5,1,2,5,10,20,50,100,200nM；Taxol treatment concentration be 0,1,2,5,10,20,50,100,
200、500nM；The concentration for the treatment of of vinorelbine be 0,5,10,20,50,100,200,500,1000,2000nM；Adriamycin processing
Concentration is 0,20,50,100,200,500,1000,2000,5000；10000nM.Chemotherapeutics handles 72h respectively, removes supernatant,
Add 0.2ml DMSO, ELIASA 570nM wavelength detecting OD values.
(2) experimental result
1 is the results are shown in Table, after handling 72 hours, median lethal dose of the Docetaxel to SK-hep-1 and SK-cbt-2 cells
(IC50) 5.3 and 231.7nM are respectively may be about, SK-cbt-2 resistance coefficient is 43.7 times or so.
Taxol respectively may be about 7.2 and 421.3nM to the IC50 of SK-hep-1 and SK-cbt-2 cells, and SK-cbt-2's is resistance to
Medicine coefficient is 57.9 times or so.
Vinorelbine respectively may be about 5.8 and 164.4nM to the IC50 of SK-hep-1 and SK-CBT-2 cells, SK-CBT-2's
Resistance coefficient is 27.9 times or so；
Adriamycin respectively may be about 78.3 and 1066.6nM to the IC50 of SK-hep-1 and SK-CBT-2 cells, SK-CBT-2's
Resistance coefficient is 13.6 times or so.
Table 1
Embodiment 2
LY2228820 detects to SK-cbt-2 cytotoxicities, selects the safe concentration without obvious cytotoxicity.
(1) experimental method
SK-hep-1 and SK-cbt-2 is inoculated in 100mm culture dishes, cultivates 72 hours, removes nutrient solution；0.25% pancreatin
Digestion, cell is collected, cell count, prepares the single cell suspension of 20000/ml concentration, inoculation 0.2ml is unicellular per hole respectively
Suspension is 4000 per hole total cell number to 96 orifice plates；Overnight incubation, be separately added into LY2228820 (concentration for the treatment of 0,10,
20th, 50,100,200,500,1000,2000,5000nM) processing 72h, removes supernatant, adds 0.2ml DMSO, ELIASA 570nM
Wavelength detecting OD values.
(2) experimental result
As a result Fig. 1 is seen, after 1000nM LY2228820 is handled 72 hours, the survival of SK-hep-1 and SK-cbt-2 cells
Rate is all still more than 90%.LY2228820 is when be less than 1000nM for this explanation, handles 72 hours to SK-hep-1 and SK-cbt-2 all
There is no obvious lethal effect.Safety effect concentration of the present invention selection 500nM LY2228820 as sensitizer, respectively with it is more
Western taxol, taxol, vinorelbine and adriamycin medication, the sensitization of the detection more chemotherapeutics of LY2228820.
Embodiment 3
LY2228820 significantly increases lethal effect of the Docetaxel to SK-cbt-2 cells.
(1) experimental method
SK-cbt-2 is inoculated in 100mm culture dishes, cultivates 72 hours, removes nutrient solution；0.25% pancreatin digests, and collects thin
Born of the same parents, cell count, the single cell suspension of 20000/ml concentration is prepared, is inoculated with 0.2ml single cell suspensions per hole respectively to 96 holes
The 2-11 row of plate, it is 4000 per hole total cell number；Overnight incubation, the 2nd row are not added with any reagent, and the cell of 3-11 row is every
Kong Doujia 500nM LY2228820, at the same be sequentially added into 2,5,10,20,50,100,200,500,1000nM) west more is purple
China fir alcohol, coprocessing processing 72h, removes supernatant, adds 0.2ml DMSO, ELIASA 570nM wavelength detecting OD values.
(2) experimental result
As a result see Fig. 2,500nM LY2228820 and Docetaxel drug combination, Docetaxel can be significantly increased
To the lethal effect of SK-cbt-2 cells.
Embodiment 4
LY2228820 significantly increases lethal effect of the taxol to SK-cbt-2 cells.
(1) experimental method
SK-cbt-2 is inoculated in 100mm culture dishes, cultivates 72 hours, removes nutrient solution；0.25% pancreatin digests, and collects thin
Born of the same parents, cell count, the single cell suspension of 20000/ml concentration is prepared, is inoculated with 0.2ml single cell suspensions per hole respectively to 96 holes
The 2-11 row of plate, it is 4000 per hole total cell number；Overnight incubation, the 2nd row are not added with any reagent, and the cell of 3-11 row is every
Kong Doujia 500nM LY2228820, at the same be sequentially added into 5,10,20,50,100,200,500,1000,2000nM) it is purple
China fir alcohol, coprocessing processing 72h, removes supernatant, adds 0.2ml DMSO, ELIASA 570nM wavelength detecting OD values.
(2) experimental result
As a result see Fig. 3,500nM LY2228820 and paclitaxel plus medication, taxol can be significantly increased to SK-cbt-
The lethal effect of 2 cells.
Embodiment 5
LY2228820 significantly increases lethal effect of the vinorelbine to SK-cbt-2 cells.
(1) experimental method
SK-cbt-2 is inoculated in 100mm culture dishes, cultivates 72 hours, removes nutrient solution；0.25% pancreatin digests, and collects thin
Born of the same parents, cell count, the single cell suspension of 20000/ml concentration is prepared, is inoculated with 0.2ml single cell suspensions per hole respectively to 96 holes
The 2-11 row of plate, it is 4000 per hole total cell number；Overnight incubation, the 2nd row are not added with any reagent, and the cell of 3-11 row is every
Kong Doujia 500nM LY2228820, at the same be sequentially added into 2,5,10,20,50,100,200,500,1000nM) Changchun is auspicious
Shore, coprocessing processing 72h, removes supernatant, adds 0.2ml DMSO, ELIASA 570nM wavelength detecting OD values.
(2) experimental result
As a result see Fig. 4,500nM LY2228820 and vinorelbine plus medication, vinorelbine can be significantly increased to SK-
The lethal effect of cbt-2 cells.
Embodiment 6
LY2228820 significantly increases lethal effect of the adriamycin to SK-cbt-2 cells.
(1) experimental method
SK-cbt-2 is inoculated in 100mm culture dishes, cultivates 72 hours, removes nutrient solution；0.25% pancreatin digests, and collects thin
Born of the same parents, cell count, the single cell suspension of 20000/ml concentration is prepared, is inoculated with 0.2ml single cell suspensions per hole respectively to 96 holes
The 2-11 row of plate, it is 4000 per hole total cell number；Overnight incubation, the 2nd row are not added with any reagent, and the cell of 3-11 row is every
Kong Doujia 500nM LY2228820, while it is sequentially added into 0.02,0.05,0.1,0.2,0.5,1,2,5 μM) adriamycin,
Coprocessing handles 72h, removes supernatant, adds 0.2ml DMSO, ELIASA 570nM wavelength detecting OD values.
(2) experimental result
As a result see Fig. 5,500nM LY2228820 and adriamycin medication, adriamycin can be significantly increased to SK-cbt-
The lethal effect of 2 cells.
Claims (9)
1. applications of the compound L Y2228820 in antineoplastic chemotherapy medicine sensitizer is prepared.
2. application as claimed in claim 1, it is characterised in that the tumour is liver cancer, cancer of pancreas, cholangiocarcinoma, breast cancer, knot
Intestinal cancer, lung cancer or oophoroma.
3. application as claimed in claim 2, it is characterised in that the tumour is liver cancer.
4. application as claimed in claim 1, it is characterised in that the chemotherapeutics is that taxol, Docetaxel, Changchun are auspicious
Shore, vincristine or adriamycin.
5. antineoplastic pharmaceutical compositions, it is characterised in that including chemotherapeutics and sensitizer, the sensitizer is compound
LY2228820。
6. antineoplastic pharmaceutical compositions as claimed in claim 5, it is characterised in that the tumour is liver cancer, cancer of pancreas, bile duct
Cancer, breast cancer, colon cancer, lung cancer or oophoroma.
7. antineoplastic pharmaceutical compositions as claimed in claim 6, it is characterised in that the tumour is liver cancer.
8. antineoplastic pharmaceutical compositions as claimed in claim 5, it is characterised in that the tumour produces to the chemotherapeutics
Drug resistance.
9. antineoplastic pharmaceutical compositions as claimed in claim 5, it is characterised in that the chemotherapeutics is taxol, more west
Taxol, vinorelbine, vincristine or adriamycin.
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| CN201710653204.9A CN107349427A (en) | 2017-08-02 | 2017-08-02 | Applications and antineoplastic pharmaceutical compositions of the compound L Y2228820 in antineoplastic chemotherapy medicine sensitizer is prepared |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017117182A1 (en) * | 2015-12-29 | 2017-07-06 | Board Of Regents, The University Of Texas System | Inhibition of p38 mapk for the treatment of cancer |
-
2017
- 2017-08-02 CN CN201710653204.9A patent/CN107349427A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017117182A1 (en) * | 2015-12-29 | 2017-07-06 | Board Of Regents, The University Of Texas System | Inhibition of p38 mapk for the treatment of cancer |
Non-Patent Citations (4)
| Title |
|---|
| CAMPBELL R. M.，ET AL: ""Characterization of LY2228820 Dimesylate, a Potent and Selective Inhibitor of p38 MAPK with Antitumor Activity"", 《MOLECULAR CANCER THERAPEUTICS》 * |
| PATNAIK A.,ET AL.: "A First-in-Human Phase I Study of the Oral p38 MAPK Inhibitor, Ralimetinib (LY2228820 Dimesylate), in Patients with Advanced Cancer", 《CLINICAL CANCER RESEARCH》 * |
| 何丹: ""p38抑制剂BIRB796逆转膜转运蛋白ABCB1介导的肿瘤多药耐药作用及其机制研究"", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
| 邱建武 等: "p38MAPK在肝细胞癌中的研究进展", 《世界华人消化杂志》 * |
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