CN106333951A - Application of mTOR kinase inhibitor and MAPK kinase inhibitor composition - Google Patents
Application of mTOR kinase inhibitor and MAPK kinase inhibitor composition Download PDFInfo
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- CN106333951A CN106333951A CN201510828267.4A CN201510828267A CN106333951A CN 106333951 A CN106333951 A CN 106333951A CN 201510828267 A CN201510828267 A CN 201510828267A CN 106333951 A CN106333951 A CN 106333951A
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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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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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
- A61K31/435—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
- A61K31/436—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 six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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Abstract
The invention relates to an application of an mTOR kinase inhibitor and MAPK kinase inhibitor composition in the preparation of medicines for treating Rheb-Y35N mutated tumors. The composition is formed by mixing a compound I with a compound II according to a mass ratio of 1:5 to 1:20. The compound I and the compound II respectively have an inhibition effect on proliferation, clone formation and survival of Rheb-Y35N mutated cells, and the compound I and the compound II are combined to substantially improve the inhibition effect of above detection indexes, so the composition can be used in the preparation of the medicines for treating Rheb-Y35N mutated tumors.
Description
Technical field
The present invention relates to mtor kinase inhibitor described herein and erk kinase inhibitor combine and their pharmaceutically acceptable salt-forming compounds treatments carry rheb-y35n mutation tumor cancer patient method, belong to pharmaceutical technology field.
Background technology
Cancer has become the primary killer of Global Health at this stage, and numerous studies show that gene mutation has inseparable relation with cancer.The mutation of gene not only leads to the change translated and albumen synthesizes to also result in the generation of carcinogenic metabolites, and the material such as these albumen or metabolite is not have or minimal amount of in script normal cell.The change of above-mentioned substance certainly will also along with intracellular signaling pathway change.So substantial amounts of antitumor drug is also using signal path as target spot, by adjusting thus playing the effect of suppression cancer to corresponding signal path.
Have now been found that pi3k/akt/mtor signal path has abnormal activation in a variety of tumor diseases.Multiple molecules in this signal path, have high-frequency mutation in a lot of cancers.As pi3kca, akt1, tsc1/2, mtor, pten etc..The result of these kinase mutants leads to the activation of this signal path, thus have activated downstream tumor cell proliferation and dividing the transcription and translation of necessary gene and promote formation and the propagation of tumor cell.According to the mutation of these kinases, a variety of inhibitor for different kinases in basic research and are clinically all being employed.Some inhibitor achieve preferably curative effect.Rheb (ras homolog enriched in brain) is one important reporter molecule of pi3k/akt/mtor signal path, and it is the homologous protein of little g albumen ras, has the activity of gtp enzyme.Rheb has two kinds of existing waies in vivo, the mode (gdp-rheb) being combined with gdp and the mode (gtp-rheb) being combined with gtp, the latter has corresponding biologic activity, by activating downstream mtor complex, phosphorylation ps6k/ps6/4e-bp-1 again, thus promote the translation process of albumen.Nearest research finds that rheb gene has high-frequency activated mutant in tumor patient.As shown in table 1, the frequency that rheb mutation occurs in different tumors.It can be seen that the frequency that rheb undergos mutation in renal carcinoma and carcinoma of endometrium is higher, and based on many mutation with rheb-y35n type.Source of data (tcga＆cbioportal datasets).
The frequency that table 1 rheb mutation occurs in different tumors
This mutation can be spontaneous the phosphorylation leading to downstream mtor albumen composition, accelerate propagation and the division of tumor cell.Verified have rheb mutation cell in, mtor signal path by idiopathic activation, lead to downstream gene transcription and abnormal cell proliferation and division.And the cell of rheb mutation can also suppress ampk and activation mapk signal path.But mtor and mapk signal path is not activated in the cancerous cell not having rheb mutation.
Mapk (mitogen-activated protein kinase), mitogen activated protein kinase, support tumor cell to be formed as other one and the signal path of propagation is also to have had been found that abnormal activation in a variety of tumors.By the TYR kinases receptors phosphorylation above having, ras-gtp/ras in active cell, thus phosphorylation braf/craf complex, phosphorylation mek/erk again, enter nucleus after erk phosphorylation and participate in transcribing and stimulating cellular proliferation of downstream gene, survival rate, the behavior such as transfer.On this signal path, the mutation of kras and braf is most commonly seen in tumor, in human lung cancer, melanoma, in the many kinds cancer such as cancer of pancreas, has had been found that high-frequency mutation.
Because rheb mutation relates generally to the activation of above-mentioned two signal path, so can effectively suppress tumor cell proliferation using mtor inhibitor and mapk inhibitor in the cell having rheb-y35n mutation, tumor cell clone is formed and suppression cell survival rate, but effect inconspicuous in the cancerous cell not having rheb-y35n mutation.Therefore, both inhibitor is used in combination has very big potential applicability in clinical practice in the tumor having rheb-y35n mutation.This is with accurate medical science, the cancer of different molecular pathological to be carried out with targeted therapy to provide new approaches.
At present the application in the medicine of the tumor in treatment rheb-y35n mutation with regard to the compositionss mentioned in the present invention is not yet reported.
Content of the invention
The present invention relates to the discovery of the medicine of tumor for the treatment of rheb mutation, one of purpose is to provide the compositionss with mtor kinases and mapk kinase inhibitory activity, for treating the tumor that rheb-y35n mutation leads to；The two of purpose are the Therapeutic Method setting up the tumor that a kind of new rheb mutation leads to.
Described compound is mtor kinase inhibitor rapamycin, is shown in formula ()；Compound is mapk kinase inhibitor, sch772984, is shown in formula ()；In compositionss, compound and the mass ratio of compound are 1:5 to 1:20.
Including but do not limit to: the said composition pharmaceutically application in the medicine of the acceptable carrier or excipient tumor in preparation treatment rheb-y35n mutation.
Experiment shows, heretofore described compositionss are with respect to being used alone compound or compound, the survival rate of the propagation of cell, Clone formation and suppression cell of rheb-y35n mutation can be significantly inhibited, therefore can be used for preparing the medicine of the tumor for the treatment of rheb-y35n mutation.
Brief description
Fig. 1 .rapamycin joint inhibitory action to 293 cell proliferation having transfected rheb-y35n mutant for the sch772984.
The inhibitory action of the nih3t3 cell survival that Fig. 2 .rapamycin joint sch772984 is mutated to rheb-y35n.A cell viability analysis b number of cell clones is taken pictures and quantitative analysises
Fig. 3. it is to suppress in mice body, to carry the inhibitory action of the tumour growth of rheb-y35n mutation with rapamycin joint sch772984.A gross tumor volume compare b tumor body photo c tumor weight compare d Mouse Weight change compare.
Specific embodiment
In conjunction with example, the present invention will be further described.Example is only limitted to the present invention is described, rather than limitation of the invention.
The solution preparation of embodiment 1 mtor kinase inhibitor and mapk kinase inhibitor.It is 20mm that rapamycin and sch772984 is prepared into storing liquid concentration with dmso dissolving respectively.Rapamycin adds culture fluid and is diluted to 20nm, and sch772984 adds culture fluid and is diluted to 200nm as working concentration.
The embodiment 2 rapamycin joint inhibitory action to 293 cell proliferation having transfected rheb-y35n mutant for the sch772984.
It is incubated at the rheb-y35n gene rotaring redyeing 293 cell of wild type and saltant type in the dmem culture fluid containing 10%fbs, add 2mm L-Glutamine, be placed in 5%co2, in 37 DEG C of incubator.Under the puromycin of 2ug/ml screens, set up the stable cell line of expression rheb-y35n saltant type and wild type.In the sch772984 Combined Treatment cell 48 hours of rapamycin and 200nm of 20nm, carry out cytotoxicity analysis with cell titer glo method, then carry out significance (t-test) analysis.Its result is as shown in Figure 1, the wild type control group with respect to same dosing for the mutation group individually adding rapamycin and individually adding sch772984, cell viability all decreases, rapamycin and sch772984 drug combination group, significantly reduces with respect to matched group and two groups of independent medication group cell viabilities.
The inhibitory action to the nih3t3 cell survival carrying rheb-y35n mutation for the embodiment 3 rapamycin joint sch772984.
Nih3t3 cell culture condition is as described above, process cell in the sch772984 of the rapamycin joint 200nm of 20nm 48 hours, carry out cytotoxicity analysis with cell titer glo method and with colony formation, then detection carries out significance (t-test) analysis.Its result is as shown in Figure 2, the transfection cell of mutant and the cell line of transfected wild-type, individually rapamycin and independent sch772984 treatment group are with respect to matched group, Clone formation quantity all has reduction, rapamycin and sch772984 drug combination group, significantly reduces with respect to matched group and two groups of independent medication group Clone formation quantity.
The inhibitory action to the tumour growth carrying rheb-y35n mutation in mice body for the embodiment 4 rapamycin joint sch772984.
Collecting transfection has the tumor cell of rheb-y35n mutation resuspended with pbs buffer salt solution, counts, and the tumor cell that transfection is had rheb mutation plants nude mice upper (5 × 10 in hypodermic mode6An individual/mice, resuspended with 100 μ lpbs), mice is divided into four groups (n=5 × 4), no medicine group, individually (calculated according to Mouse Weight to rapamycin group, dosage is 3mg/kg), can individually give sch772984 (25mg/kg) group and administering drug combinations group.After tumor planting mice is subcutaneous, treat tumor size length to 300mm3Proceed by administration to process, once every three days, drug administration by injection, the measurement of mouse interior tumor size was surveyed once in 2-3 days, altogether continued 21 days.Gross tumor volume is pressed following equation and is calculated: (l × w2)/2. simultaneously to mouse tumor Taking Pictures recording and weight weighs, monitoring Mouse Weight change in every three days.Assess the inhibition to tumour growth for the combination medicine process by contrasting matched group, finally carry out significance (t-test) analysis.Its result is as shown in Figure 3, individually rapamycin and independent sch772984 treatment group are with respect to matched group, tumor volume and tumor weight all have reduction, rapamycin and sch772984 drug combination group, all significantly reduce with respect to matched group and two groups of independent medication group above-mentioned two indexs, and Mouse Weight does not have notable difference.
Shown by above-mentioned experiment, can effectively suppress tumor cell proliferation in the cell having rheb-y35n mutation using mtor inhibitor and mapk inhibitor, tumor cell clone is formed and suppression cell survival rate.Therefore, the exploitation being used in combination as cancer therapy drug of both inhibitor provides candidate scheme, has very big potential applicability in clinical practice in the tumor having rheb-y35n mutation.
Claims (3)
1. a kind of mtor kinase inhibitor and the compositionss of mapk kinase inhibitor are in preparation treatment
Rheb-y35n mutation the medicine of tumor in application it is characterised in that: described compound
For mtor kinase inhibitor rapamycin, its structural formula is formula ()；Compound is
Mapk kinase inhibitor, sch772984, its structural formula is formula ().
2. according to claim 1 application it is characterised in that: compound and change in compositionss
The mass ratio of compound is 1:5 to 1:20.
3. according to claim 1 and 2 application it is characterised in that: include said composition medicine
The medicine of the acceptable carrier or excipient tumor in preparation treatment rheb-y35n mutation on
Application in thing.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113853218A (en) * | 2020-01-22 | 2021-12-28 | 中国科学院上海营养与健康研究所 | Application of MAPK/ERK pathway inhibitor in antagonizing skin aging and radiation-induced skin premature aging |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015095829A1 (en) * | 2013-12-20 | 2015-06-25 | Biomed Valley Discoveries, Inc. | Cancer treatments using combinations of pi3k/akt pathway and erk inhibitors |
| WO2015095831A1 (en) * | 2013-12-20 | 2015-06-25 | Biomed Valley Discoveries, Inc. | Cancer treatments using combinations of mtor and erk inhibitors |
| WO2015160986A2 (en) * | 2014-04-16 | 2015-10-22 | Infinity Pharmaceuticals, Inc. | Combination therapies |
| WO2015168599A1 (en) * | 2014-05-02 | 2015-11-05 | The Wistar Institute Of Anatomy And Biology | Combination therapies targeting mitochondria for cancer therapy |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015095829A1 (en) * | 2013-12-20 | 2015-06-25 | Biomed Valley Discoveries, Inc. | Cancer treatments using combinations of pi3k/akt pathway and erk inhibitors |
| WO2015095831A1 (en) * | 2013-12-20 | 2015-06-25 | Biomed Valley Discoveries, Inc. | Cancer treatments using combinations of mtor and erk inhibitors |
| WO2015160986A2 (en) * | 2014-04-16 | 2015-10-22 | Infinity Pharmaceuticals, Inc. | Combination therapies |
| WO2015168599A1 (en) * | 2014-05-02 | 2015-11-05 | The Wistar Institute Of Anatomy And Biology | Combination therapies targeting mitochondria for cancer therapy |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113853218A (en) * | 2020-01-22 | 2021-12-28 | 中国科学院上海营养与健康研究所 | Application of MAPK/ERK pathway inhibitor in antagonizing skin aging and radiation-induced skin premature aging |
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Granted publication date: 20181102 Termination date: 20211124 |