CN105854018B - Wnt inhibitor is preparing the application in treating hematopoiesis aplastic disease drug - Google Patents
Wnt inhibitor is preparing the application in treating hematopoiesis aplastic disease drug Download PDFInfo
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- CN105854018B CN105854018B CN201610183285.6A CN201610183285A CN105854018B CN 105854018 B CN105854018 B CN 105854018B CN 201610183285 A CN201610183285 A CN 201610183285A CN 105854018 B CN105854018 B CN 105854018B
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- 230000011132 hemopoiesis Effects 0.000 title claims abstract description 21
- 239000003112 inhibitor Substances 0.000 title claims abstract description 18
- 201000010099 disease Diseases 0.000 title claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 title claims abstract description 12
- 229940079593 drug Drugs 0.000 title claims abstract description 8
- HQWTUOLCGKIECB-XZWHSSHBSA-N (6S,9aS)-6-[(4-hydroxyphenyl)methyl]-8-(1-naphthalenylmethyl)-4,7-dioxo-N-(phenylmethyl)-3,6,9,9a-tetrahydro-2H-pyrazino[1,2-a]pyrimidine-1-carboxamide Chemical compound C1=CC(O)=CC=C1C[C@H]1C(=O)N(CC=2C3=CC=CC=C3C=CC=2)C[C@H]2N1C(=O)CCN2C(=O)NCC1=CC=CC=C1 HQWTUOLCGKIECB-XZWHSSHBSA-N 0.000 claims abstract description 39
- 101000616738 Homo sapiens NAD-dependent protein deacetylase sirtuin-6 Proteins 0.000 claims abstract description 28
- 102100021840 NAD-dependent protein deacetylase sirtuin-6 Human genes 0.000 claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 108010013043 Acetylesterase Proteins 0.000 claims 1
- 102000005421 acetyltransferase Human genes 0.000 claims 1
- 108020002494 acetyltransferase Proteins 0.000 claims 1
- 210000000130 stem cell Anatomy 0.000 abstract description 26
- 230000008929 regeneration Effects 0.000 abstract description 9
- 238000011069 regeneration method Methods 0.000 abstract description 9
- 210000003958 hematopoietic stem cell Anatomy 0.000 abstract description 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 230000005764 inhibitory process Effects 0.000 abstract description 2
- 230000010534 mechanism of action Effects 0.000 abstract description 2
- 230000001737 promoting effect Effects 0.000 abstract description 2
- 238000003209 gene knockout Methods 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 230000014509 gene expression Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 210000005259 peripheral blood Anatomy 0.000 description 4
- 239000011886 peripheral blood Substances 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000006870 function Effects 0.000 description 3
- 230000002607 hemopoietic effect Effects 0.000 description 3
- 230000003463 hyperproliferative effect Effects 0.000 description 3
- 238000011813 knockout mouse model Methods 0.000 description 3
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- WOVKYSAHUYNSMH-UHFFFAOYSA-N BROMODEOXYURIDINE Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-UHFFFAOYSA-N 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- 230000035519 G0 Phase Effects 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 229950004398 broxuridine Drugs 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/07—Tetrapeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0075—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the delivery route, e.g. oral, subcutaneous
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biotechnology (AREA)
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Abstract
The present invention discloses Wnt inhibitor ICG001 and is preparing the application in treating hematopoiesis aplastic disease drug.Wnt inhibitor ICG001 is by the Wnt signal paths for inhibiting CBP to mediate, the exhaustion of the candidate stem cell of excessively high Wnt signals caused by being lacked by SIRT6 to inhibition.Disclosed herein ICG001 can be used for preparing the mechanism of action of the drug and ICG001 for the treatment of hematopoiesis aplastic relevant disease for promoting SIRT6 knockout hematopoietic stem cell regenerations.
Description
Technical field
The invention belongs to biomedical class technical fields, are related to Wnt inhibitor ICG-001 and are preparing treatment hematopoiesis aregeneratory
Application in property disease medicament.
Background technology
Hemopoietic system carries human body transport oxygen and nutriment to each histocyte, while by carbon dioxide and metabolism
Product transports external function, and as body occur damage stress and to it is anti-infective when, scheduling teacher of immune systems at different levels,
It is body update and most fast one of the tissue of reproduction speed, in the marrow of the mankind, there are about the new of trillion (about 1012) meter daily
Cell generates.Hemopoietic system is the histoorgan with most strong power of regeneration in human body, however in many hematopoiesis aplastics
It is the hematopoiesis aregeneratory caused by candidate stem cell function reduction caused by certain gene function defects in disease,
Seriously affect health even life.Most cells in candidate stem cell are in nondividing vegetative state, i.e. quiescent stage (G0
Phase).And sub-fraction only therein has active proliferative capacity, and until move towards terminal differentiation.And this tranquillization
Function is considered to have crucial biological significance.Studies have shown that this sub-fraction maintains tranquillization always in candidate stem cell
The cell of phase can preferably resist radiation, cytotoxin, oxidative stress, thus can exist all the life, to meet the need of hematopoiesis
It asks.However in clinical and experiment, hematopoietic stem cell transplantation can lead to hematopoiesis due to the variation of some intracellular signaling pathway
System reconstructing ability declines or the exhaustion of candidate stem cell.Therefore, effective treatment hematopoiesis aplastic disease drug is found
As clinically aplastic bone marrow venereal disease human needs.
The regulation and control of candidate stem cell stable state are a complicated polymolecular participation process, in order to illustrate the tune of this complex process
Section mechanism, scientific research personnel often using various gene knock-out mice models come study signal specific access to candidate stem cell self more
New and differentiation influence.Wnt signal paths cell proliferation in the stem cell of many types has played key effect, in recent years
Research confirms that Wnt has an effect on stem cell differentiation, and regulates and controls to the self-renewing of candidate stem cell.
Wnt inhibitor ICG001 is micromolecular compound, CAS number：780757-88-2, molecular weight 548.63 are changed
Be named as (6S, 9aS) -6- (4-hydroxybenzyl)-N-benzyl-8- (naphthalen-1-ylmethyl) -4,7-
Dioxo-hexahydro-2H-pyrazino [1,2-a] pyrimidine-1 (6H)-carboxa mide, molecular formula are
C33H32N4O4, chemical constitution is as follows：
In this item patent, applicant has found applications of the ICG001 in hematopoiesis aplastic relevant disease for the first time.Tool
Body, this patent finds that ICG001 can play the effect for inhibiting Wnt signals in vivo, reduces as caused by Wnt signals are excessively high
The exhaustion of excessive cell Proliferation and stem cell.This item patent also discloses it and is used for the work of hematopoiesis aplastic relevant disease
Use mechanism.ICG001 inhibits the activity of CBP albumen in hematopoiesis regenerative process, and reducing Wnt signals prevents hyper-proliferative maintenance from making
Hemocytoblast stable state.
Invention content
The purpose of the present invention is in view of the above-mentioned problems, proposing Wnt inhibitor ICG001 is preparing treatment hematopoiesis regeneration barrier
Application in impenetrability disease medicament.
The present invention is using SIRT6 knock-out mices in candidate stem cell as model.It is found by the applicant that compound ICG001 can press down
The activity and then inhibition Wnt signal genes of CPB albumen processed are expressed, and the expression of Wnt signal genes is inhibited SIRT6 can be promoted to knock out
The regeneration of mouse hematopoietic stem cell reduces the hyper-proliferative of cell.Simultaneously it has also been found that give Wnt inhibitor ICG001 in vitro can
Play identical effect.Result above discloses effects and mechanism of the ICG001 in promoting hematopoiesis regeneration.
The effective dose of ICG001 is 3.2mg/kg, and drug is made into solvent, is administered in a manner of being injected intraperitoneally.
The beneficial effects of the invention are as follows ICG001, and SIRT6 can be promoted to knock out hematopoietic stem cell regeneration.ICG001 can be reduced
SIRT6 knocks out the hyper-proliferative of candidate stem cell.Disclosed herein ICG001 can be used for preparing treatment hematopoiesis aplastic
The mechanism of action that the drug and ICG001 of relevant disease are used to that SIRT6 to be promoted to knock out hematopoietic stem cell regeneration.
Description of the drawings
Fig. 1, which is SIRT6 gene knockouts, can increase Wnt signal path gene expressions；
Fig. 2 is that ICG001 inhibits Wnt signal path gene expressions in SIRT6 knock out mice bodies；
Fig. 3 is peripheral blood reconstruction ability and the hematopoiesis that ICG001 processing can improve SIRT6 gene knockout candidate stem cells
The reconstruction ability of stem cell；
Fig. 4 is the Wnt signal paths that ICG001 inhibits SIRT6 gene knockout candidate stem cells under conditions of cultivating in vitro
Gene expression；
Fig. 5 is the peripheral blood reconstruction energy that the processing of ICG001 in vitro cultures can improve SIRT6 gene knockout candidate stem cells
The reconstruction ability of power and candidate stem cell；
Fig. 6 is mechanism flow chart of the present invention.
Specific implementation mode
With reference to embodiment and attached drawing, the present invention is further illustrated, rather than limiting the invention.
SIRT6 gene knockouts (the SIRT6 that the present invention uses△/△) mouse and cleaning grade C57BL/6 Mouse feeders be in Hangzhou
Normal university's Experimental Animal Center cleaning grade animal house, mouse is 6-8 week old when experiment.During entire experiment in vivo, institute
There is operation to abide by what national and Ethics Committee of Hangzhou Pedagogic University formulated《Experimental animal uses regulations》.ICG001 is purchased from U.S.
State LC Laboratories；Dimethyl sulfoxide (DMSO) (Dimethyl sulfoxide, DMSO), 5- bromodeoxyuridine nucleosides (5-
Bromo-2-deoxyUridine, BRDU) etc. from Sigma-Aldrich buy；It is all used in the present invention
Antibody is purchased from Cell Signaling Technology companies of the U.S. except illustrating.All experimental results are by only
Vertical three repeated experiments obtain, and using unpaired t check analysis data, are indicated with scholar SEM.P values<0.05 is conspicuousness
Difference criteria (*<0.05, * *<0.01).
Embodiment one：Wnt inhibitor ICG001 can promote the regeneration of SIRT6 gene knockout candidate stem cells
The candidate stem cell of separation and Extraction SIRT6 gene knockouts and littermate control wild-type mice is detected and is analyzed and compares
Gene expression difference and SIRT6 lack the influence to hematopoietic stem cell transplantation ability between two groups.The result shows that SIRT6 clpp genes
Except the HSC of mouse can dramatically increase Wnt signal paths gene expression (Fig. 1).After vivo medicine-feeding 3 times, ICG001 is in SIRT6 genes
Wnt signal paths gene expression (Fig. 2) is significantly inhibited in knock-out mice body.It is tested by bone-marrow transplantation, compares ICG001 processing
Group, it can be found that the peripheral blood that ICG001 significantly improves SIRT6 gene knockout candidate stem cells rebuilds ability and candidate stem cell
Reconstruction ability (Fig. 3).ICG001 also inhibits the Wnt of SIRT6 gene knockout candidate stem cells to believe under conditions of cultivating in vitro
Number pathway gene expression (Fig. 4).The processing of ICG001 in vitro cultures can improve the peripheral blood of SIRT6 gene knockout candidate stem cells
The reconstruction ability (Fig. 5) of reconstruction ability and candidate stem cell.
The above result shows that Wnt inhibitor ICG001 can promote the regeneration of SIRT6 gene knockout candidate stem cells.Such as
Shown in Fig. 6, Wnt inhibitor ICG001 can prevent the marrow failure of SIRT6 gene knockout hemopoietic systems and treat by SIRT6 bases
The hematopoiesis aplastic relevant disease caused by knockout.
Above-described embodiment is not for the limitation of the present invention, and the present invention is not limited only to above-described embodiment, as long as meeting
The present invention claims all belong to the scope of protection of the present invention.
Claims (3)
- Application in 1.Wnt inhibitor hematopoiesis aplastic disease drug caused by preparing treatment SIRT6 and knocking out, wherein Wnt inhibitor is to inhibit the active Wnt inhibitor ICG001 of acetyl transferase CBP.
- 2. Wnt inhibitor as described in claim 1 hematopoiesis aplastic disease medicine caused by preparing treatment SIRT6 and knocking out Application in object, it is characterised in that the Wnt inhibitor ICG001 is micromolecular compound, CAS number 780757- 88-2, molecular weight 548.63, chemical name are (6S, 9aS) -6- (4-hydroxybenzyl)-N-benzyl-8- (naphthalen-1-ylmethyl)-4,7-dioxo-hexahydro-2H-pyrazino[1,2-a]pyrimidine-1 (6H)-carboxamide, molecular formula C33H32N4O4, chemical constitution is as follows：
- 3. Wnt inhibitor as described in claim 1 hematopoiesis aplastic disease medicine caused by preparing treatment SIRT6 and knocking out Application in object, it is characterised in that acetylase CBP is the target spot of Wnt signal paths, and Wnt inhibitor ICG001 is by directly pressing down Wnt signal paths processed prevent cell hyperproliferation.
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| CN201610183285.6A CN105854018B (en) | 2016-03-28 | 2016-03-28 | Wnt inhibitor is preparing the application in treating hematopoiesis aplastic disease drug |
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| CN105854018B true CN105854018B (en) | 2018-11-13 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111450109A (en) * | 2020-05-06 | 2020-07-28 | 武汉大学 | Application of cyclic adenosine monophosphate and derivatives thereof in resisting EV71 virus |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113476454B (en) * | 2021-08-16 | 2023-07-18 | 河南省儿童医院郑州儿童医院 | Application of ICG-001 in preparation of medicine for treating autism |
| CN114209837B (en) * | 2021-12-29 | 2023-07-14 | 中山大学附属第五医院 | Medicament for treating erectile dysfunction and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7563825B1 (en) * | 2005-03-18 | 2009-07-21 | Choongwae Pharma Corporation | Modulation of beta-catenin coactivator interactions to effect stem cell growth or differentiation |
| CN103476415A (en) * | 2010-11-16 | 2013-12-25 | 南加州大学 | CBP/catenin antagonists for enhancing asymmetric division of somatic stem cells |
| WO2014025832A1 (en) * | 2012-08-06 | 2014-02-13 | University Of Southern California | Wnt modulators for the protection, mitigation and treatment of radiation injury |
| CN104586840A (en) * | 2015-01-07 | 2015-05-06 | 杭州师范大学 | Application of Wip1 inhibitor in preparing medicine for treating liver regeneration deficiency diseases |
-
2016
- 2016-03-28 CN CN201610183285.6A patent/CN105854018B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7563825B1 (en) * | 2005-03-18 | 2009-07-21 | Choongwae Pharma Corporation | Modulation of beta-catenin coactivator interactions to effect stem cell growth or differentiation |
| CN103476415A (en) * | 2010-11-16 | 2013-12-25 | 南加州大学 | CBP/catenin antagonists for enhancing asymmetric division of somatic stem cells |
| WO2014025832A1 (en) * | 2012-08-06 | 2014-02-13 | University Of Southern California | Wnt modulators for the protection, mitigation and treatment of radiation injury |
| CN104586840A (en) * | 2015-01-07 | 2015-05-06 | 杭州师范大学 | Application of Wip1 inhibitor in preparing medicine for treating liver regeneration deficiency diseases |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111450109A (en) * | 2020-05-06 | 2020-07-28 | 武汉大学 | Application of cyclic adenosine monophosphate and derivatives thereof in resisting EV71 virus |
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