CN110433164A - The application of TGF-beta acceptor molecule inhibitor acute myeloid leukemia in treatment mouse model - Google Patents
The application of TGF-beta acceptor molecule inhibitor acute myeloid leukemia in treatment mouse model Download PDFInfo
- Publication number
- CN110433164A CN110433164A CN201910751244.6A CN201910751244A CN110433164A CN 110433164 A CN110433164 A CN 110433164A CN 201910751244 A CN201910751244 A CN 201910751244A CN 110433164 A CN110433164 A CN 110433164A
- Authority
- CN
- China
- Prior art keywords
- tgf
- acute myeloid
- beta
- myeloid leukemia
- aml
- 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.)
- Pending
Links
- 208000031261 Acute myeloid leukaemia Diseases 0.000 title claims abstract description 42
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 title claims abstract description 25
- 102000004887 Transforming Growth Factor beta Human genes 0.000 title claims abstract description 25
- 108090001012 Transforming Growth Factor beta Proteins 0.000 title claims abstract description 25
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 title claims abstract description 25
- 239000003112 inhibitor Substances 0.000 title claims abstract description 21
- 238000011282 treatment Methods 0.000 title claims abstract description 18
- 238000010172 mouse model Methods 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 4
- 230000004663 cell proliferation Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 210000003714 granulocyte Anatomy 0.000 abstract description 9
- 210000000952 spleen Anatomy 0.000 abstract description 8
- 238000010322 bone marrow transplantation Methods 0.000 abstract description 7
- 210000004072 lung Anatomy 0.000 abstract description 7
- 230000035755 proliferation Effects 0.000 abstract description 5
- 210000002798 bone marrow cell Anatomy 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 3
- 230000005012 migration Effects 0.000 abstract description 2
- 238000013508 migration Methods 0.000 abstract description 2
- 208000032839 leukemia Diseases 0.000 description 35
- 210000004027 cell Anatomy 0.000 description 27
- 241000699670 Mus sp. Species 0.000 description 26
- 241000699666 Mus <mouse, genus> Species 0.000 description 24
- 210000000130 stem cell Anatomy 0.000 description 15
- 101150105104 Kras gene Proteins 0.000 description 13
- 108091006044 chimera Proteins 0.000 description 12
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 230000001154 acute effect Effects 0.000 description 8
- 210000001185 bone marrow Anatomy 0.000 description 8
- 230000014509 gene expression Effects 0.000 description 8
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 229960000684 cytarabine Drugs 0.000 description 7
- 210000004989 spleen cell Anatomy 0.000 description 7
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 6
- 229960000975 daunorubicin Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- 208000025113 myeloid leukemia Diseases 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 101150040459 RAS gene Proteins 0.000 description 5
- 229960002685 biotin Drugs 0.000 description 5
- 235000020958 biotin Nutrition 0.000 description 5
- 239000011616 biotin Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 230000004913 activation Effects 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 101100289995 Caenorhabditis elegans mac-1 gene Proteins 0.000 description 3
- 102100030708 GTPase KRas Human genes 0.000 description 3
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 230000002607 hemopoietic effect Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 231100000590 oncogenic Toxicity 0.000 description 3
- 230000002246 oncogenic effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 102000016914 ras Proteins Human genes 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 101150069832 CD2 gene Proteins 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- 206010064571 Gene mutation Diseases 0.000 description 2
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 2
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 2
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 208000014767 Myeloproliferative disease Diseases 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 2
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 2
- 108091005735 TGF-beta receptors Proteins 0.000 description 2
- 102000016715 Transforming Growth Factor beta Receptors Human genes 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 230000001332 colony forming effect Effects 0.000 description 2
- 101150036876 cre gene Proteins 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 102200006539 rs121913529 Human genes 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000011830 transgenic mouse model Methods 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- 208000031404 Chromosome Aberrations Diseases 0.000 description 1
- 108010051219 Cre recombinase Proteins 0.000 description 1
- 102100029974 GTPase HRas Human genes 0.000 description 1
- 101710113436 GTPase KRas Proteins 0.000 description 1
- 102100039788 GTPase NRas Human genes 0.000 description 1
- 101000584633 Homo sapiens GTPase HRas Proteins 0.000 description 1
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- IBCXZJCWDGCXQT-UHFFFAOYSA-N LY 364947 Chemical compound C=1C=NC2=CC=CC=C2C=1C1=CNN=C1C1=CC=CC=N1 IBCXZJCWDGCXQT-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101000652434 Mus musculus Protein SON Proteins 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 102000001759 Notch1 Receptor Human genes 0.000 description 1
- 108010029755 Notch1 Receptor Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108010091086 Recombinases Proteins 0.000 description 1
- 102000018120 Recombinases Human genes 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 108020005038 Terminator Codon Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000011950 custard Nutrition 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 239000003540 gamma secretase inhibitor Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000002360 granulocyte-macrophage progenitor cell Anatomy 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 210000005096 hematological system Anatomy 0.000 description 1
- 210000000777 hematopoietic system Anatomy 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 238000001325 log-rank test Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 201000011649 lymphoblastic lymphoma Diseases 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000011242 molecular targeted therapy Methods 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 230000000869 mutational effect Effects 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000009984 peri-natal effect Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 108700042226 ras Genes Proteins 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000008672 reprogramming Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 201000003624 spinocerebellar ataxia type 1 Diseases 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
- A61K31/435—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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (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 applications of TGF-beta acceptor molecule inhibitor ly364947 acute myeloid leukemia (AML) in treatment mouse model.Specifically, the present invention provides the new applications of TGF-beta receptor-I type micromolecular inhibitor ly364947.The inhibitor can inhibit grain-macrophage progenitors in-vitro multiplication in AML mouse bone marrow cells, effectively extend the life cycle of AML bone-marrow transplantation gomphosis mouse, inhibit proliferation of the leukemic granulocytes in spleen and the migration in lungs.The present invention clinically treats AML for TGF-beta acceptor inhibitor and provides certain experimental basis.
Description
Technical field
The invention belongs to field of biotechnology, and in particular to a kind of TGF-beta receptor-I type molecule inhibitor is small in treatment
The application of acute myeloid leukemia in rat animal model.
Background technique
Acute myeloid leukemia (Acute Myeloid Leukemia, AML) be with marrow with it is original and young in peripheral blood
The Malignancy that young marrow cell paraplasm is characterized.In recent years, as that studies AML deepening continuously and curing
The continuous improvement for the treatment of technology, the therapeutic effect of AML and prognosis, which obtain, greatly to be improved, but it is still not fully up to expectations, only 40%~
50% AML patient obtains long term survival (Bertoli, S., et al., Therapy-related acute myeloid
Leukemia following treatment of lymphoid malignancies.Oncotarget, 2016.).Therefore,
Seeking safer, efficient AML treatment method is emphasis and difficulties urgently to be resolved at present.Present complex treatment be with
Based on bone marrow transplantation therapy, supplemented by radiation and chemotherapy, and the new method for combining the biological therapies such as immune and molecule is being inquired into.
The regulatory molecule for controlling normal development is often related to malignant tumour, and ras-MAPK kinase pathway is exactly wherein most heavy
One of leukaemia pathogenesis wanted.There are three hypotypes for RAS gene: HRAS, NRAS and KRAS, and KRAS is that human hematopoietic system is disliked
Property disease occurs most frequently one of gene of mutation, and occurs mainly in medullary system and T cell system malignant disease, seldom betides B
Cell line (Zhang, J., et al., Oncogenic Kras-induced leukemogeneis:hematopoietic
stem cells as the initial target and lineage-specific progenitors as the
Potential targets for final leukemic transformation.Blood, 2009.113:p.1304-
1314.).The heredity for having the human acute myeloid leukemia researches show that 20-26% ratio to be found to have RAS proto-oncogene at present lacks
Fall into (Eisfeld, A., et al, The mutational oncoprint of recurrent cytogenetic
Abnormalities in adult patients with de novo acute myeloid leukemia.Leukemia,
2017.10:p.2211-2218.).The mutation of 12,13 codons of KRAS gene causes the GTP enzymatic activity of RAS albumen to reduce,
Promote G12D mutain to be in the sustained activation state in conjunction with GTP, thus the enhancing of RAS signal can be caused, so as to cause
The sustained activation of KRAS albumen, cause cell proliferation and differentiation, vicious transformation etc. change (Shaw, R.J.and L.C.Cantley,
Ras, PI (3) K and mTOR signalling controls tumour cell growth.Nature, 2006.441
(7092): p.424-30.Cazzola, M., M.G Della Porta, and L.Malcovati, The genetic basis
Of myelodysplasia and its clinical relevance.Blood, 2013.122 (25): p.4021-34.).
One of the most common mutation in leukaemia of Kras gene is the sweet ammonia of Kras exon 2 encoded by codon 12
Acid mutation is aspartic acid, LSL-KrasGl2DIt includes turn of the both ends with loxp that mouse, which is then in the upstream of the mutation,
Terminator codon is recorded, can be cut off by Cre recombinase, so as to cause the carcinous Kras gene (Kras of mutationGl2D/+) expression
(Braun, B.S., et al., Somatic activation of oncogenic Kras in hematopoietic
cells initiates a rapidly datal myeloproliferative disorder.Proc Natl Acad
Sci U S A, 2004.101 (2): p.597-602.).Cre transgenic mice can knock out two sides in specific tissue and have Loxp
The gene order of point, and the expression of Cre gene is controlled by CD2 gene in CD2-Cre mouse.CD2 gene is mainly expressed in into mouse
Hemopoietic system in lymph stem/progenitor cells, natural kill and its precursor, all Plasmacytoids and~20% traditional tree
Prominent shape cell, thus recombinase mainly acts on the hematopoietic cell of blood forming organ in CD2-Cre, is for establishing hemopoietic system spy
Effective tool (Siegemund, S., et al., hCD2-iCre the and Vav-iCre of heterologous gene expression or missing
Mediated gene recombination patterns in murine hematopoietic cells.PLoS One,
2015.10 (4): p.e0124661.).
The Kras of early stageG12D/+Transgenosis and bone-marrow transplantation are in hemopoietic system research shows that a variety of phenotypes, including medullary system increase
Natural disposition disease or T cell leukaemia (Chan IT, et al.Conditional expression of oncogenic K-ras
from its endogenous promoter induces a myeloproliferative disease.J Clin
Invest.2004；113 (4): 528-538.Kindler, T., et al., K-RasG12D-induced T-cell
lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to
Gamma-secretase inhibitors.Blood, 2008.112 (8): p.3373-82.).These researchs mostly utilize
The Kras of MxCre1 induction adult miceG12D/+Oncogene expression.Recently, the Kras of Vav-iCre and Flt3-Cre inductionG12D/+
Embryonic-period mice expression cause it is antenatal lethal or develop into perinatal period medullary system granulocytic leukemia (Tang, P., et al.,
Differential roles of Kras and Pten in murine leukemogenesis.Leukemia, 2013.27
(5): p.1210-4.Tarnawsky, S.P., et al., Mice expressing KrasG12D in hematopoietic
Multipotent progenitor cells develop neonatal myeloid leukemia.J Clin Invest,
2017.127 (10): p.3652-3656.).This research has utilized LSL-KrasGl2DMouse and CD2-Cre mouse are established
KrasGl2D/+The mouse model of the hematological system specific gene mutation of expression obtains KrasGl2D/+The genotype of stable and consistent expression
Mouse, observing its phenotype is acute myeloid leukemia.We find target molecule mechanism downstream, signal path conduction in an experiment
It is to be regulated and controled by TGF-beta signal path.Therefore, for TGF-beta signal path or the molecular targeted therapy of its receptor
Drug is discussion emphasis of this research in acute myeloid granulocytic leukemia drug therapy.
Patent No. US8298825 discloses a kind of multiple target point kinases inhibitor, they have TGF-beta receptor
Very strong inhibiting effect.Wherein, there is the compound of inhibiting effect to TGF-beta receptor-I type, as shown in following formula (I), chemistry
Entitled 4- [3- (2-pyridinyl) -1H-pyrazol-4-yl]-quinoline, (4- [3- (2- pyridyl group) -1H- pyrazoles -4-
Base]-quinoline).Before studies have shown that ly364947 can be used for the preparation of reprogramming of somatic cells, and apply small in chronic peritonitis
Mouse model, pancreatic cancer cell tumor xenograft and oncogene BCR-ABL activation chronic myelogenous leukemia treatment in
(Naka, K., et al., TGF-b-FOXO signalling maintains leukaemia-initiating cells in
Chronic myeloid leukaemia.Nature, 2010.463:p.676-680), imply that ly364947 is possibly used for treating
Above-mentioned disease, but it is not directed to gene genetic background and the true acute myeloid leukemia of etiology unknown.
Summary of the invention
The object of the present invention is to provide a kind of TGF-beta receptor-I type molecule inhibitors to treat in mouse model
The application of acute myeloid leukemia.The present invention provides a kind of purposes of TGF-beta receptor-I type inhibitor, are used to prepare (i)
Inhibit the proliferation of AML cell, and/or the pharmaceutical composition of (ii) treatment acute myeloid leukemia.
It is a discovery of the invention that acute myeloid granulocyte of the TGF-beta receptor-I type molecule inhibitor for mouse model
Leukaemia has good therapeutic effect.In a preferred embodiment of the present invention, small point of-I type of the TGF-beta receptor
Sub- inhibitor is compound or pharmaceutically acceptable salt thereof shown in following formula (I).In the present invention, the TGF-beta receptor-I type suppression
The dosage of preparation can be measured in 1-20mg/kg, preferably 10mg/kg, the dosage in the form of compound (I).
Ability can also be made in formula (I) compound or its pharmaceutically acceptable salt together with pharmaceutically acceptable carrier
Form known to domain, such as tablet, capsule, granule, injection.The present invention relates to containing selected from formula (I) compound or its
The compound of pharmaceutically acceptable salt prepares the purposes in the drug for treating aforementioned acute myeloid leukemia in animal model.
Detailed description of the invention
Fig. 1 shows that compound (I) processing inhibits leukaemia grain-macrophage progenitor cells GMP in M3434 medium body outgrowth energy
Power.
Fig. 2 shows that the treatment that acute myeloid leukemia Chi-meric mice life cycle is established to bone marrow transplanted mice is applied alone in compound (I)
Effect, and use daunorubicin AraC and cytarabine DNR Chemotherapeutic treatments as control.
Fig. 3 show compound (I) be applied alone to bone marrow transplanted mice establish acute myeloid leukemia Chi-meric mice curative effect (lung,
The hematoxylin-eosin HE dyeing display leukaemia cell of hepatic tissue invades profit).Arrow indicates leukaemia cell in lungs and liver
Invade profit site.
Fig. 4 show compound (I) be applied alone influence bone marrow transplanted mice establish acute myeloid leukemia Chi-meric mice marrow and
From the counting and fluidic cell phenotype of blood infected seed-macrophage progenitors and leukaemia cell in spleen.(A)CD45.1+Receptor
Leukaemia grain-macrophage progenitor cells the GMP and marrow series leukemia granulocyte of the donor CD45.2 positive in mouse bone marrow cells and spleen cell
Mac+Gr1+Flow cytometry.(B)CD45.1+Recipient mice marrow and spleen cell count.(C)CD45.1+Recipient mice bone
Leukaemia grain-macrophage progenitor cells the GMP and marrow series leukemia granulocyte Mac of the donor CD45.2 positive in marrow and spleen cell+Gr1+
Statistical chart.Control is drug untreated fish group.
Specific embodiment
The present inventor reports a kind of TGF-beta receptor-I molecule inhibitor ly364947 in the white blood of acute myeloid for the first time
The application of disease.The experimental results showed that ly364947, that is, compound (I) inhibits in acute myeloid leukemia mouse from blood infected seed-macrophage
The proliferation of progenitor cells, the result of experiment in vivo further demonstrate that ly364947 treatment extends acute myeloid leukemia bone-marrow transplantation
The life cycle of Chi-meric mice, it is suppressed that leukaemia cell significantly reduces AML leukaemia in the proliferation of spleen and the transfer of lungs
Grain-macrophage progenitor cells GMP and marrow series leukemia granulocyte Mac-1+Gr1+In the proliferation and differentiation of marrow and spleen.This is use
TGF-beta receptor-I molecule inhibitor clinically treats AML and provides certain experimental basis.
With reference to embodiments for further describing the present invention, but these embodiments are not intended to limit the scope of the invention.
Test medicine
Test-compound (I) configuration method: being dissolved in DMSO with 5mg/mL, and is diluted in 100 μ L physiological saline.
Experimental animal
The B6.129S4-Kras of expressing K ras gene G12D mutaintm4Tyj/ J mouse, and contain locus specificity CD2
B6.Cg-Tg (CD2-icre) 4Kio/J transgenic mice of promoter, it is public purchased from U.S. The Jackson Laboratory
Department.The mating breeding of this two Strains of Mouse, constitutes the filial generation hybrid mice Kras for carrying double transgenicG12D/+；CD2cre+For
Acute myeloid leukemia mouse model.Single sun of littermate or jack to jack adapter mouse son are control.CD45.1+ phenotype
B6.SJL-CD45.1 (Ly5.1) is bone marrow transplant recipient mouse, is purchased from Department Of Medicine, Peking University's animal center.The above mouse exists
Medical University Of Tianjin's animal center captive breeding.Feeding environment: SPF grades.
Immunocyte phenotype: grain-macrophage progenitors (granulocyte-macrophage progenitor,
GMP): Lineage-Sca-1-c-kit+CD16/32h1CD34+, granulocyte (myeloid cells) .Mac-1+Gr1+, Hematopoietic Stem
Cell (KLS): Lineage-Sca-1+c-kit+。
Experimental procedure
Mouse colony forms unit detection (Colony-forming-unit assay, CFU Assay)
Prepare MethoCult 3434 (methylcellulose semisolid) culture medium, is purchased from STEM CELL company.Fluidic cell
Instrument preparation control and KrasG12D/+；CD2Cre+The marrow GMP cell of mouse has dispensed the addition of suitable cell concentration
In 3434 semisolid culturemedium of MethoCult and it is inoculated with.37 DEG C, containing 5%CO2, under the conditions of humidity >=95%, cultivate 14 days left sides
CFU colony is detected on the right side.
FCM analysis and sorting (Flow cytometry, FACS)
Conventional method handles and obtains mouse bone marrow cells or Spleen mononuclear cell.For GMP cell analysis or sorting, use
Magnetic bead (CD117 MieroBeads, mouse are purchased from Mlitenyi Biotec company) enrichment c-kit positive cell.In cell
In surface antibody label, GMP cell analysis and sorting use an antiantibody for (Biotin anti-CD4, Biotin anti-
CD8, Biotin anti-B220, Biotin anti-Ter119, Biotin anti-Mac1, Biotin-Gr1), cell incubation
After being resuspended with washing, secondary antibody antibody incubation (Lin is used--APC-Cy7)(Sca1-PE-Cy7)(c-kit-APC)(CD34-
FITC)(CD16/32-PE)(CD45.1-PECy5)(CD45.2-PerCy5.5).Medullary system granulocyte uses Mac1-PE-Cy7,
Gr1-FITC label.The above antibody is purchased from BD Pharmingen or eBioscience company.All data BD
LSRFortessa or FACSAria III (BD company) is collected, and is analyzed with FlowJo software (Tree Star, Inc.).
Bone-marrow transplantation establishes AML Chi-meric mice
Choose 32 6-8 weeks Recipient mice (CD45.1+), lethal dose radiation irradiation (9.0Gy) is irradiated in two times, is spaced
4h, single dose 4.5Gy.The preprepared CD45.2 of every tail vein injection of mouse after irradiation+KrasG12D/+；
CD2Cre+The myelomonocyte suspension of acute myeloid leukemia mouse, every injection volume are 0.2ml (1 × 106cells).It moves
Mouse after plant, raising supplements the nutrients in added with antibiotic in SPF grades of environment, drinking water, daily Feeding with Eggs custard, in order to avoid mouse
Since irradiation causes the death rate to increase, survival state is recorded daily.10 days progress drug-treateds after transplanting, are divided into four groups, 8/
Group: (1) control group: the intraperitoneal injection diluted DMSO of PBS；(2) Ly364947 group: intraperitoneal injection 10mgkg-1/2days；(3)
Cytarabine (Cytarabine, AraC): intraperitoneal injection 50mgkg-1/ days is injected 5 days；(4) cytarabine/daunorubicin
(AraC+DNR): cytarabine 50mgkg is injected intraperitoneally in first five day-1/ days starts to inject daunorubicin on the 6th day
(Daunorubicin, DNR) 1mgkg-1/ 2days is injected 6 times.Record each group life cycle situation daily.
Zooscopy is ratified by Nankai University's animal care and using the committee.All zooperies are according to US National
The nursing of Institutes of Health Research experimental animal and guide for use (NIH, the 8th edition, 2011) are carried out.Through Ethics Committee, Nankai University batch
It is quasi-.
Data analysis
Data are analyzed with GraphPad Prism 6.Comparison among groups Student t-test.P value < 0.05 is considered as statistics
It is significant on.
Embodiment 1
Compound (I) processing inhibits leukaemia grain-macrophage progenitor cells GMP growth in vitro in M3434 culture medium ability.
We, which assess, inhibits TGF-beta signal path in KrasG12D/+With the leukaemia mechanism of WT GMP.Firstly,
It sorts GMP cell to handle using compound (I), and is induced in MethoCult 3434 (methylcellulose semisolid) culture medium
In-vitro multiplication and differentiation (Colony forming experiment, CFU assay).As a result it is huge to observe that compound (I) significantly inhibits leukaemia grain-
Bite progenitor cells KrasG12D/+The growth ability (Fig. 1) of the CFU Colony forming sum of GMP.This proves that TGF-beta signal path is
KrasG12DImportant downstream effect albumen, compound (I) treatment influence leukaemia grain-macrophage progenitor cells ex vivo growth capability.
Embodiment 2
Evaluation compound (I), chemotherapeutics daunorubicin AraC and cytarabine DNR establish bone marrow transplanted mice acute
The curative effect of marrow series leukemia Chi-meric mice.
As a result, it has been found that AraC and two groups of mouse death rates of AraC/DNR are very high, and begin within the 4th day after administration dead
It dies, mean survival time (MST) is 16 and 17 days (Fig. 2).DMSO control group survival state is put down close to two groups of mouse of AraC and AraC/DNR
Equal life cycle is 22 days.Compound (I) organizes survival rate highest, wherein the life span extension of 5 Chi-meric mices is more than 100 days (Fig. 2).
Log-rank test is analysis shows that P=0.0109, compound (I) vs control group.Therefore, compound (I), which is applied alone, obviously inhibits small
The development of acute myeloid granulocytic leukemia in mouse bone marrow transplant model.This make it is presumed that, traditional clinical treatment is simultaneously
Kras cannot effectively be treatedG12D/+AML caused by gene mutation can cause by force mouse too early very much due to the pharmacological property of chemotherapeutic instead
Death, and the generation process of leukaemia can be effectively relieved in the molecule inhibitor compounds (I) for targeting TGF-β signal path.
Embodiment 3
The lung of bone-marrow transplantation AML Chi-meric mice, the hematoxylin-eosin HE dyeing of hepatic tissue, display compound (I) are applied alone effectively
AML leukaemia cell is inhibited to invade profit.Arrow indicates that leukaemia cell invades profit site in lungs and liver.
We analyze the histology of the bone-marrow transplantation gomphosis mouse each group of week old matching.Compound (I) substantially reduces
AML cell invades profit and migration (Fig. 3) liver and lungs.Thus, TGF-beta receptor-I inhibitor compound (I) is effective
Prevent KrasG12D/+The lethality of leukaemia prompts KrasG12D/+；CD2Cre+Leukaemia cell may be in TGF-beta defect
Weaken its pernicious canceration ability in microenvironment.
Embodiment 4
Compound (I) is applied alone leukaemia grain-macrophage ancestral in the marrow and spleen for influencing bone marrow transplanted mice AML Chi-meric mice thin
Born of the same parents GMP and Mac+Gr1+The counting and fluidic cell phenotype of marrow series leukemia cell.(A)CD45.1+Recipient mice marrow and spleen
Leukaemia grain-macrophage progenitor cells the GMP and marrow series leukemia granulocyte Mac of the donor CD45.2 positive in cell+Gr1+Fluidic cell
Analysis.(B)CD45.1+Recipient mice marrow and spleen cell count.(C)CD45.1+It is supplied in Recipient mice marrow and spleen cell
Leukaemia grain-macrophage progenitor cells the GMP and marrow series leukemia granulocyte Mac of the body CD45.2 positive+Gr1+Statistical chart.
For the situation of life cycle, we take marrow to compound (I) group and the untreated control group A ML Chi-meric mice of drug
It is counted (Fig. 4 B) with spleen, compound (I) significantly reduces the marrow and spleen cell number of AML Chi-meric mice.Also, in order to see
The variation of its cellular level is examined, the marrow and spleen cell of the above Chi-meric mice have done FCM analysis, it has been found that compound (I)
Group leukaemia grain-macrophage progenitor cells (GMP) and maturation grain-monocyte (Mac-1+Gr1+) also have the tendency that substantially reducing (figure
4A, C).
Conclusion
The obvious development for inhibiting acute myeloid granulocytic leukemia in bone marrow transplanted mice model is applied alone in compound (I), and
Extend life cycle.Compared to the chemotherapeutics of more conventional acute myeloid granulocytic leukemia, daunorubicin and cytarabine, compound
(I) there are obvious curative effects.Result above prompt compound (I) can effectively assist the treatment of acute myeloid leukemia.
It is incorporated as referring in this application in the document that the present invention refers to.In addition, it should also be understood that, of the invention having read
After above content, this field research and development and technical staff can be made various changes or modifications the present invention, and such equivalent forms are same
Sample is fallen within the scope of the appended claims of the present application.
Claims (3)
- The application of 1.TGF-beta acceptor molecule inhibitor acute myeloid leukemia in treatment mouse model, described in selection TGF-beta acceptor molecule inhibitor is TGF-beta receptor-I type micromolecular inhibitor ly364947.It is characterized in that, being used for Prepare the pharmaceutical composition that (i) inhibits AML cell Proliferation, and/or (ii) treatment acute myeloid leukemia.
- 2. purposes according to claim 1, wherein the TGF-beta receptor-I type micromolecular inhibitor is formula (I) institute Show compound or pharmaceutically acceptable salt thereof,
- 3. purposes according to claim 2, wherein the dosage of the TGF-beta receptor-I type micromolecular inhibitor is 1-20mg/kg, preferably 10mg/kg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910751244.6A CN110433164A (en) | 2019-08-15 | 2019-08-15 | The application of TGF-beta acceptor molecule inhibitor acute myeloid leukemia in treatment mouse model |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910751244.6A CN110433164A (en) | 2019-08-15 | 2019-08-15 | The application of TGF-beta acceptor molecule inhibitor acute myeloid leukemia in treatment mouse model |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110433164A true CN110433164A (en) | 2019-11-12 |
Family
ID=68435612
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910751244.6A Pending CN110433164A (en) | 2019-08-15 | 2019-08-15 | The application of TGF-beta acceptor molecule inhibitor acute myeloid leukemia in treatment mouse model |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110433164A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021105317A1 (en) * | 2019-11-28 | 2021-06-03 | Origo Biopharma, S.L. | Benzylamide derivatives as inhibitors of transforming growth factor-beta receptor i/alk5 |
| CN115282280A (en) * | 2022-08-12 | 2022-11-04 | 中国科学技术大学 | New use of TGF-beta 1 signal inhibitor |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013253065A (en) * | 2012-06-08 | 2013-12-19 | Kanazawa Univ | Therapeutic agent for chronic myelogenous leukemia and screening method for the agent |
-
2019
- 2019-08-15 CN CN201910751244.6A patent/CN110433164A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013253065A (en) * | 2012-06-08 | 2013-12-19 | Kanazawa Univ | Therapeutic agent for chronic myelogenous leukemia and screening method for the agent |
Non-Patent Citations (3)
| Title |
|---|
| BENJAMIN S. BRAUN ET AL: "Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder", PNAS, vol. 101, no. 2, pages 597 - 602, XP055013490, DOI: 10.1073/pnas.0307203101 * |
| 杨丽媛 等: "TGF-β信号通路抑制剂LY364947对急性髓系白血病细胞增殖、凋亡和侵袭的影响", 中国细胞生物学学报, vol. 41, no. 2, pages 256 - 264 * |
| 陈占国: "AML1-ETO融合蛋白致急性髓系白血病机制及靶向治疗", 微循环学, vol. 24, no. 3, pages 81 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021105317A1 (en) * | 2019-11-28 | 2021-06-03 | Origo Biopharma, S.L. | Benzylamide derivatives as inhibitors of transforming growth factor-beta receptor i/alk5 |
| CN114787145A (en) * | 2019-11-28 | 2022-07-22 | 奥里戈生物制药有限公司 | Benzamide derivatives as transforming growth factor-beta receptor I/ALK5 inhibitors |
| CN114787145B (en) * | 2019-11-28 | 2024-03-26 | 阿戈麦布西班牙股份有限公司 | Benzamide derivatives as transforming growth factor-beta receptor I/ALK5 inhibitors |
| CN115282280A (en) * | 2022-08-12 | 2022-11-04 | 中国科学技术大学 | New use of TGF-beta 1 signal inhibitor |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Kielbassa et al. | Understanding the origin and diversity of macrophages to tailor their targeting in solid cancers | |
| JP2022113722A (en) | Methods and compositions for ex vivo expansion of human hematopoietic stem/progenitor cells | |
| Chang et al. | Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice | |
| Chen et al. | TSC–mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species | |
| Lu et al. | IFN-γ and indoleamine 2, 3-dioxygenase signaling between donor dendritic cells and T cells regulates graft versus host and graft versus leukemia activity | |
| Burgess et al. | Preclinical efficacy of MEK inhibition in Nras-mutant AML | |
| Larochelle et al. | Engraftment of immune-deficient mice with primitive hematopoietic cells from β-thalassemia and sickle cell anemia patients: implications for evaluating human gene therapy protocols | |
| TW201930592A (en) | SgRNA construct, method for increase the expression level of the fetal hemoglobin and application and use thereof | |
| Portwood et al. | Activity of the hypoxia-activated prodrug, TH-302, in preclinical human acute myeloid leukemia models | |
| Helgason et al. | Homeostasis and regeneration of the hematopoietic stem cell pool are altered in SHIP-deficient mice | |
| CN110433164A (en) | The application of TGF-beta acceptor molecule inhibitor acute myeloid leukemia in treatment mouse model | |
| Rankin et al. | Insights gained from modelling high‐grade glioma in the mouse | |
| Dumas et al. | Dual inhibition of FLT3 and AXL by gilteritinib overcomes hematopoietic niche-driven resistance mechanisms in FLT3-ITD acute myeloid leukemia | |
| Van Etten et al. | The Ph-positive and Ph-negative myeloproliferative neoplasms: some topical pre-clinical and clinical issues | |
| Qiu et al. | Autophagy inhibition impairs leukemia stem cell function in FLT3-ITD AML but has antagonistic interactions with tyrosine kinase inhibition | |
| Mehrpouri et al. | The contributory roles of histone deacetylases (HDACs) in hematopoiesis regulation and possibilities for pharmacologic interventions in hematologic malignancies | |
| CN101560496A (en) | Dendritic cell carried by tumor stem cell antigen and subjected to tolerance screening, preparation method and application thereof, kit and vaccine comprising dendritic cell | |
| Yamamoto et al. | Functionally deregulated AML1/RUNX1 cooperates with BCR-ABL to induce a blastic phase-like phenotype of chronic myelogenous leukemia in mice | |
| JP2018162974A (en) | Hematopoietic organ tumor therapeutic agent, and screening method | |
| CN109628396A (en) | The application of memory lymphocyte group in the treatment of liver cancer | |
| Joshi et al. | Leukemia stem cells in the pathogenesis, progression, and treatment of acute myeloid leukemia | |
| Fischer et al. | MCL1 dependence across MDS subtypes and dual inhibition of MCL1 and BCL2 in MISTRG6 mice | |
| CN114134177B (en) | Setd5 knockout mouse model and acute T lymphocyte leukemia resisting mouse model construction method and application | |
| WO2023085673A1 (en) | Ut2 gene-deficient mouse model and method for screening therapeutic agent for myeloid leukemia, using same | |
| Fernandes et al. | PS1450 THE PHARMACOLOGICAL IGF1R‐IRS1/2 INHIBITOR OSI‐906 REDUCES ERYTHROID PROGENITORS AND INHIBITS STAT3 IN JAK2V617F KNOCKIN‐MYELOPROLIFERATIVE NEOPLASM MICE |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20191112 |
|
| WD01 | Invention patent application deemed withdrawn after publication |