CN106333951B - A kind of application of mTOR kinase inhibitors and the composition of mapk kinase inhibitor - Google Patents
A kind of application of mTOR kinase inhibitors and the composition of mapk kinase inhibitor Download PDFInfo
- Publication number
- CN106333951B CN106333951B CN201510828267.4A CN201510828267A CN106333951B CN 106333951 B CN106333951 B CN 106333951B CN 201510828267 A CN201510828267 A CN 201510828267A CN 106333951 B CN106333951 B CN 106333951B
- Authority
- CN
- China
- Prior art keywords
- rheb
- mutation
- composition
- cell
- tumour
- 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.)
- Expired - Fee Related
Links
- 0 CC*C*NCC Chemical compound CC*C*NCC 0.000 description 2
Classifications
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to a kind of application of the composition of mTOR kinase inhibitors and mapk kinase inhibitor in preparing the drug of tumour for the treatment of Rheb-Y35N mutation.It is characterized in that：The composition is chemical compounds I and compound ii by 1:5 to 1:20 (mass ratioes) mix.
Description
Technical field
The present invention relates to mTOR kinase inhibitors described herein and ERK kinase inhibitors combination and their pharmacy
The method that upper acceptable salt-forming compound treatment carries the tumour cancer patient of Rheb-Y35N mutation, belongs to medical science neck
Domain.
Background technology
Cancer has become the primary killer of Global Health at this stage, numerous studies show gene mutation and cancer have it is close not
The relationship that can divide.The change that the mutation of gene not only causes translation and albumen to synthesize also results in the generation of carcinogenic metabolites, and
Either the substances such as metabolin are no or minimal amount of in script normal cell to these albumen.The change of above-mentioned substance is bound to
Also along with the change of intracellular signaling pathway.So a large amount of antitumor drug is also to be passed through using signal path as target spot
To the adjusting of corresponding signal path to play the role of pressing down cancer.
Have now been found that PI3K/AKT/mTOR signal paths have abnormal activation in a variety of tumor diseases.The signal
Multiple molecules in access, there is high-frequency mutation in many cancers.Such as PI3KCA, AKT1, TSC1/2, mTOR, PTEN
Deng.The result of these kinase mutants leads to the activation of the signal path, must to have activated downstream tumor cell proliferation and division
The transcription and translation of the gene needed and formation and the proliferation for promoting tumour cell.According to the mutation of these kinases, many kinds are directed to
The inhibitor of different kinases is all being applied in basic research and clinically.Some inhibitor achieve curative effect preferable.
Rheb (Ras homolog enriched in brain) is one important reporter molecule of PI3K/AKT/mTOR signal paths,
It is the homologous protein of small G-protein Ras, the activity with GTP enzymes.There are two types of existing ways in vivo by Rheb, are combined with GDP
Mode (GDP-Rheb) and the mode (GTP-Rheb) that is combined with GTP, the latter there is corresponding biological activity, pass through activation
Downstream mTOR compounds, then phosphorylation pS6K/pS6/4E-BP-1, to promote the translation process of albumen.Nearest research hair
Existing Rheb genes have high-frequency activated mutant in tumor patient.As shown in table 1, Rheb mutation occur in different tumours
Frequency.It can be seen that the frequency that Rheb mutates in kidney and carcinoma of endometrium is higher, and mostly it is mutated with Rheb-Y35N types
Based on.Data source (TCGA&Cbioportal datasets).
1 Rheb of table is mutated the frequency occurred in different tumours
The mutation can be spontaneous the phosphorylation for leading to downstream mTOR albumen compositions, accelerate tumour cell proliferation and
Division.It is verified in the cell for thering is Rheb to be mutated, mTOR signal paths by spontaneous activation, cause downstream gene transcribe and
Abnormal cell proliferation and division.And the cell of Rheb mutation can also inhibit AMPK and activation MAPK signal paths.But
There is no mTOR and MAPK signal paths in the cancer cell of Rheb mutation not to be activated.
MAPK (mitogen-activated protein kinase), mitogen-activated protein kinase, as other one
Item supports that tumour cell is formed and the signal path of proliferation is also to have had been found that abnormal activation in a variety of tumours.By above having
Tyrosine kinases receptors phosphorylation, Ras-GTP/Ras in active cell, to phosphorylation BRAF/CRAF compounds, then phosphoric acid
Change MEK/ERK, nucleus is entered after ERK phosphorylations and participates in the transcription of downstream gene and stimulates cellular proliferation, survival rate, transfer etc.
Behavior.On the signal path, the mutation of KRAS and BRAF are most commonly seen in tumour, in human lung cancer, melanoma, cancer of pancreas
Deng in a variety of cancers, high-frequency mutation has been had been found that.
Since Rheb mutation relate generally to the activation of above-mentioned two signal path, so being pressed down using mTOR inhibitors and MAPK
Preparation can effectively inhibit tumor cell proliferation in the cell for having Rheb-Y35N to be mutated, and tumor cell clone is formed and suppression
Cell survival rate processed, but effect is not obvious in the cancer cell of no Rheb-Y35N mutation.Therefore, be used in combination this two
Kind inhibitor has prodigious potential applicability in clinical practice in the tumour for having Rheb-Y35N to be mutated.This is with accurate medicine to difference
The cancer of molecular pathology parting carries out targeted therapy and provides new approaches.
Application about composition mentioned in the present invention in the drug of the tumour for the treatment of Rheb-Y35N mutation at present
It has not been reported.
Invention content
The present invention relates to treatment Rheb mutation tumour drug discovery, the first purpose be to provide with mTOR kinases with
The composition of mapk kinase inhibiting effect, for treating tumour caused by Rheb-Y35N mutation；The second purpose is to establish one kind newly
Rheb mutation caused by tumour therapy.
The chemical compounds I is mTOR kinase inhibitor Rapamycin, is shown in formula (I)；Compound ii is mapk kinase
Inhibitor, SCH772984 are shown in formula (II)；The mass ratio of chemical compounds I and compound ii is 1 in composition:5 to 1:20.
Including but do not limit to：Pharmaceutically acceptable carrier or excipient are preparing treatment Rheb-Y35N to the composition
Application in the drug of the tumour of mutation.
Experiment shows heretofore described composition relative to exclusive use chemical compounds I or compound ii, Neng Gouxian
Proliferation, Clone formation and the survival rate for inhibiting cell of the cell for inhibiting Rheb-Y35N mutation are write, therefore can be used for preparing
Treat the drug of the tumour of Rheb-Y35N mutation.
Description of the drawings
Fig. 1 .Rapamycin joint SCH772984 is to having transfected the inhibition of 293 cell Proliferations of Rheb-Y35N mutant
Effect.
Inhibiting effect of Fig. 2 .Rapamycin joint SCH772984 to the Rheb-Y35N NIH3T3 cell survivals being mutated.a
Cell viability analysis b number of cell clones is taken pictures and quantitative analysis
Fig. 3 are to combine SCH772984 with rapamycin the tumour for carrying Rheb-Y35N mutation in Mice Body is inhibited to give birth to
Long inhibiting effect.A gross tumor volumes compare b knurl photo c tumor weights compare d mouse weights variation compare.
Specific implementation mode
In conjunction with example, the present invention will be further described.Example is only limitted to illustrate the present invention, rather than the limit to the present invention
It is fixed.
It is prepared by 1 mTOR kinase inhibitors of embodiment and the solution of mapk kinase inhibitor.Rapamycin and SCH772984
Respectively a concentration of 20mM of storing liquid is prepared into DMSO dissolvings.Rapamycin adds culture solution to be diluted to 20nM, and SCH772984 adds
Culture solution is diluted to 200nM as working concentration.
Embodiment 2 Rapamycin joint SCH772984 is to having transfected 293 cell Proliferations of Rheb-Y35N mutant
Inhibiting effect.
By the Rheb-Y35N gene rotaring redyeing 293 cells of wild type and saltant type, it is incubated at the DMEM cultures containing 10%FBS
In liquid, 2mM glutamine is added, 5%CO is placed in2, in 37 DEG C of incubator.Under the Puromycin screenings of 2ug/mL, establish
Express the stable cell line of Rheb-Y35N saltant types and wild type.In the SCH772984 connection of the Rapamycin and 200nM of 20nM
It closes processing cell 48 hours, carries out cytotoxicity analysis with cell Titer Glo methods, then carry out conspicuousness (T-TEST)
Analysis.The results are shown in Figure 1 for it, and individually plus Rapamycin adds the mutation group of SCH772984 relative to same dosing with independent
Wild type control group, cell viability decrease, Rapamycin and SCH772984 drug combination groups, relative to control group with
And two groups of independent medication group cell viabilities significantly reduce.
Embodiment 3 Rapamycin joint SCH772984 is to carrying the NIH3T3 cell survivals of Rheb-Y35N mutation
Inhibiting effect.
NIH3T3 cell culture conditions in the Rapamycin of 20nM as described above, combine the SCH772984 processing of 200nM
Cell 48 hours, cytotoxicity analysis is carried out with cell Titer Glo methods and with colony formation, then detection carries out
Conspicuousness (T-TEST) is analyzed.The results are shown in Figure 2 for it, transfects the cell of mutant and the cell line of transfected wild-type, individually
Relative to control group, Clone formation quantity has a reduction for Rapamycin and independent SCH772984 processing group, Rapamycin and
SCH772984 drug combination groups are significantly reduced relative to control group and two groups of independent medication group Clone formation quantity.
The tumour growth that 4 Rapamycin of embodiment joint SCH772984 are mutated to carrying Rheb-Y35N in Mice Body
Inhibiting effect.
Collecting transfection has the tumour cell that Rheb-Y35N is mutated to be resuspended with PBS buffer salt solutions, counts, transfection is had
The tumour cell of Rheb mutation plants nude mice upper (5 × 10 in a manner of hypodermic6A/mouse, with 100 μ LPBS weights
It is outstanding), mouse is divided into four groups (n=5 × 4), and no medicine group individually (calculates, dosage is to Rapamycin groups according to mouse weight
3mg/kg), SCH772984 (25mg/kg) groups and administering drug combinations group can individually be given.After tumor planting mouse is subcutaneous, tumour is waited for
Size is grown to 300mm3Administration processing is proceeded by, once every three days, drug administration by injection, the measurement of mouse interior tumor size is in 2-
It surveys once within 3 days, continues 21 days in total.Gross tumor volume is calculated according to the following formula：(L×W2It takes pictures note to mouse tumor simultaneously)/2.
It records and weight is weighed, monitor mouse weight variation every three days.Combination medicine processing is assessed to swollen by comparing control group
The inhibition of tumor growth finally carries out conspicuousness (T-TEST) and analyzes.The results are shown in Figure 3 for it, independent Rapamycin and list
Only SCH772984 processing group has reduction, Rapamycin and SCH772984 relative to control group, tumor volume and tumor weight
Drug combination group is significantly reduced relative to control group and two groups of independent medication group above-mentioned two indexs, and mouse weight does not have
There is notable difference.
Shown using mTOR inhibitors and MAPK inhibitor in the cell for thering is Rheb-Y35N to be mutated by above-mentioned experiment
Tumor cell proliferation, tumor cell clone can be effectively inhibited to form and inhibit cell survival rate.Therefore, both inhibitor
Be used in combination and provide candidate scheme for the exploitation of anticancer drug, have prodigious face in the tumour for thering is Rheb-Y35N to be mutated
Bed application prospect.
Claims (3)
1. the composition of a kind of mTOR kinase inhibitors and mapk kinase inhibitor is preparing the tumour for treating Rheb-Y35N mutation
Drug in application, it is characterised in that：The chemical compounds I is mTOR kinase inhibitor Rapamycin, and structural formula is formula
(Ⅰ)；Compound ii is mapk kinase inhibitor, and SCH772984, structural formula is formula (II),
2. application according to claim 1, it is characterised in that：The mass ratio of chemical compounds I and compound ii is in composition
1:5 to 1:20.
3. application according to claim 1 or 2, it is characterised in that：Including further including that can pharmaceutically connect in the composition
The carrier or excipient received.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510828267.4A CN106333951B (en) | 2015-11-24 | 2015-11-24 | A kind of application of mTOR kinase inhibitors and the composition of mapk kinase inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510828267.4A CN106333951B (en) | 2015-11-24 | 2015-11-24 | A kind of application of mTOR kinase inhibitors and the composition of mapk kinase inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106333951A CN106333951A (en) | 2017-01-18 |
| CN106333951B true CN106333951B (en) | 2018-11-02 |
Family
ID=57826844
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510828267.4A Expired - Fee Related CN106333951B (en) | 2015-11-24 | 2015-11-24 | A kind of application of mTOR kinase inhibitors and the composition of mapk kinase inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106333951B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113853218B (en) * | 2020-01-22 | 2023-08-25 | 中国科学院上海营养与健康研究所 | Use of MAPK/ERK pathway inhibitors for antagonizing skin aging and radiation premature skin 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 |
-
2015
- 2015-11-24 CN CN201510828267.4A patent/CN106333951B/en not_active Expired - Fee Related
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 |
|---|---|---|---|---|
| CN113853218B (en) * | 2020-01-22 | 2023-08-25 | 中国科学院上海营养与健康研究所 | Use of MAPK/ERK pathway inhibitors for antagonizing skin aging and radiation premature skin aging |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106333951A (en) | 2017-01-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20210186993A1 (en) | Combination therapies targeting mitochondria for cancer therapy | |
| WO2021032213A1 (en) | Anti-aging medicine d/s targeting aging cells in tissue microenvironment and use thereof | |
| TW202114670A (en) | A use of a combination of an ezh2 inhibitor and a cdk4/6 inhibitor in preparation of medicine for treating tumors | |
| Xie et al. | Anwulignan is a novel JAK1 inhibitor that suppresses non‐small cell lung cancer growth | |
| Zhang et al. | Advances in CD73 inhibitors for immunotherapy: antibodies, synthetic small molecule compounds, and natural compounds | |
| CN106333951B (en) | A kind of application of mTOR kinase inhibitors and the composition of mapk kinase inhibitor | |
| CN110664818B (en) | Medicine for treating lung cancer | |
| Nam et al. | Possible therapeutic targets among the molecules involved in the Warburg effect in tumor cells | |
| US20190183893A1 (en) | Low dose of sildenafil as an antitumor drug | |
| CN107583054A (en) | Cryptotanshinone pharmaceutical composition and its application in treatment chronic myelocytic leukemia medicine is prepared | |
| CN111714480A (en) | Use of anthranilic acid derivatives in the manufacture of a medicament for the treatment of cancer | |
| Wang et al. | Phosphorylation of PBK/TOPK Tyr74 by JAK2 promotes Burkitt lymphoma tumor growth | |
| CN109793727A (en) | A kind of pharmaceutical composition and its application of effective anti-malignant tumor | |
| CN109420167B (en) | Combined medicine for treating tumor | |
| Tang et al. | Ginsenoside 3β-O-Glc-DM (C3DM) suppressed glioma tumor growth by downregulating the EGFR/PI3K/AKT/mTOR signaling pathway and modulating the tumor microenvironment | |
| CN111686111B (en) | Application of MALT1 protease inhibitor in preparation of non-small cell lung cancer therapeutic drug | |
| CN115177618A (en) | Application of FLT3 inhibitor in preparation of medicine for treating acute myeloid leukemia | |
| CN110464845A (en) | A kind of combination medicine combination and its application for Breast cancer immunotherapy | |
| CN111298122B (en) | Pharmaceutical composition for treating small cell lung cancer and application thereof | |
| CN110215516A (en) | It is a kind of to inhibit the treatment of CDK5 synergetic immunity in the application inhibited in breast cancer | |
| CN103961342A (en) | Novel use of adapalene in treating cancer | |
| CN112933239A (en) | Application of reagent for activating endogenous PD-1 of tumor cells in preparation of antitumor drugs | |
| CN113440519A (en) | Application of mycophenolic acid and derivatives thereof in preparation of drugs for targeted therapy of cancers | |
| CN1301111C (en) | Use of phenoxthine compounds in preparing medicnies for inhibiting cancers and promoting radio-sensitive medicines | |
| WO2022127788A1 (en) | Application of lenvatinib and aurora-a kinase inhibitor in preparing cancer-inhibiting drugs |
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 | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20181102 Termination date: 20211124 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |