JP6527149B2 - ベータ−サラセミアの処置のための方法及び医薬組成物 - Google Patents
ベータ−サラセミアの処置のための方法及び医薬組成物 Download PDFInfo
- Publication number
- JP6527149B2 JP6527149B2 JP2016534904A JP2016534904A JP6527149B2 JP 6527149 B2 JP6527149 B2 JP 6527149B2 JP 2016534904 A JP2016534904 A JP 2016534904A JP 2016534904 A JP2016534904 A JP 2016534904A JP 6527149 B2 JP6527149 B2 JP 6527149B2
- Authority
- JP
- Japan
- Prior art keywords
- xpo1
- pharmaceutical composition
- compound
- inhibits
- phenyl
- 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
- 208000005980 beta thalassemia Diseases 0.000 title claims description 49
- 238000000034 method Methods 0.000 title claims description 42
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 37
- 108700002148 exportin 1 Proteins 0.000 claims description 83
- 101150094313 XPO1 gene Proteins 0.000 claims description 82
- 102100029095 Exportin-1 Human genes 0.000 claims description 79
- 101100485284 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CRM1 gene Proteins 0.000 claims description 79
- 150000001875 compounds Chemical class 0.000 claims description 51
- 239000003112 inhibitor Substances 0.000 claims description 41
- 108010078791 Carrier Proteins Proteins 0.000 claims description 31
- 210000003743 erythrocyte Anatomy 0.000 claims description 27
- 239000004480 active ingredient Substances 0.000 claims description 24
- 230000014509 gene expression Effects 0.000 claims description 23
- 230000035800 maturation Effects 0.000 claims description 22
- 102100031690 Erythroid transcription factor Human genes 0.000 claims description 18
- 101710100588 Erythroid transcription factor Proteins 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 14
- 108090000994 Catalytic RNA Proteins 0.000 claims description 13
- 102000053642 Catalytic RNA Human genes 0.000 claims description 13
- 108091092562 ribozyme Proteins 0.000 claims description 13
- 230000011748 cell maturation Effects 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 11
- -1 4-bromo-2,5-difluorophenyl Chemical group 0.000 claims description 10
- 108091034117 Oligonucleotide Proteins 0.000 claims description 9
- 239000000074 antisense oligonucleotide Substances 0.000 claims description 9
- 238000012230 antisense oligonucleotides Methods 0.000 claims description 9
- 230000002779 inactivation Effects 0.000 claims description 9
- 230000002708 enhancing effect Effects 0.000 claims description 8
- 230000002797 proteolythic effect Effects 0.000 claims description 8
- 238000000338 in vitro Methods 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 5
- 108020004459 Small interfering RNA Proteins 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 238000012360 testing method Methods 0.000 claims description 4
- JCHAWRDHMUSLMM-UPHRSURJSA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-1-(3,3-difluoroazetidin-1-yl)prop-2-en-1-one Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)N3CC(F)(F)C3)C=N2)=C1 JCHAWRDHMUSLMM-UPHRSURJSA-N 0.000 claims description 3
- 208000002903 Thalassemia Diseases 0.000 claims description 3
- LBNWRDCVNGUTBP-MDZDMXLPSA-N (e)-3-[3-(3-chlorophenyl)-1,2,4-triazol-1-yl]-n-(4-methoxyphenyl)prop-2-enamide Chemical compound C1=CC(OC)=CC=C1NC(=O)\C=C\N1N=C(C=2C=C(Cl)C=CC=2)N=C1 LBNWRDCVNGUTBP-MDZDMXLPSA-N 0.000 claims description 2
- RUDSDOHVAFYBTM-MDZDMXLPSA-N (e)-3-[3-(3-chlorophenyl)-1,2,4-triazol-1-yl]-n-phenylprop-2-enamide Chemical compound ClC1=CC=CC(C2=NN(\C=C\C(=O)NC=3C=CC=CC=3)C=N2)=C1 RUDSDOHVAFYBTM-MDZDMXLPSA-N 0.000 claims description 2
- LAERLYAFDFCLNM-CMDGGOBGSA-N (e)-n-(2-chlorophenyl)-3-[3-(3-chlorophenyl)-1,2,4-triazol-1-yl]prop-2-enamide Chemical compound ClC1=CC=CC(C2=NN(\C=C\C(=O)NC=3C(=CC=CC=3)Cl)C=N2)=C1 LAERLYAFDFCLNM-CMDGGOBGSA-N 0.000 claims description 2
- MQYSATPQVZDKMW-UHFFFAOYSA-N 1-(2-thiophen-2-ylethyl)pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1CCC1=CC=CS1 MQYSATPQVZDKMW-UHFFFAOYSA-N 0.000 claims description 2
- XAHCEMQKWSQGLQ-UHFFFAOYSA-N 1-(4-methoxyphenyl)pyrrole-2,5-dione Chemical group C1=CC(OC)=CC=C1N1C(=O)C=CC1=O XAHCEMQKWSQGLQ-UHFFFAOYSA-N 0.000 claims description 2
- NNBAXWAPIROUSM-UHFFFAOYSA-N 1-(4-morpholin-4-ylphenyl)pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C1=CC=C(N2CCOCC2)C=C1 NNBAXWAPIROUSM-UHFFFAOYSA-N 0.000 claims description 2
- MZOKHTDHXVAGFM-UHFFFAOYSA-N 1-[2-(4-chlorophenyl)ethyl]pyrrole-2,5-dione Chemical compound C1=CC(Cl)=CC=C1CCN1C(=O)C=CC1=O MZOKHTDHXVAGFM-UHFFFAOYSA-N 0.000 claims description 2
- UPWIXROBQHXMSV-UHFFFAOYSA-N 3-methyl-1-(1-methylpyrazol-3-yl)pyrrole-2,5-dione Chemical compound O=C1C(C)=CC(=O)N1C1=NN(C)C=C1 UPWIXROBQHXMSV-UHFFFAOYSA-N 0.000 claims description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 2
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 2
- ZIDYPKUSLUFJCE-SREVYHEPSA-N ethyl (z)-3-[3-(3-chlorophenyl)-1,2,4-triazol-1-yl]prop-2-enoate Chemical group CCOC(=O)\C=C/N1C=NC(C=2C=C(Cl)C=CC=2)=N1 ZIDYPKUSLUFJCE-SREVYHEPSA-N 0.000 claims description 2
- 230000001737 promoting effect Effects 0.000 claims description 2
- 238000012216 screening Methods 0.000 claims description 2
- VYXKJDGAVZVZAA-FPLPWBNLSA-N tert-butyl (z)-3-[3-(3-chlorophenyl)-1,2,4-triazol-1-yl]prop-2-enoate Chemical compound CC(C)(C)OC(=O)\C=C/N1C=NC(C=2C=C(Cl)C=CC=2)=N1 VYXKJDGAVZVZAA-FPLPWBNLSA-N 0.000 claims description 2
- RCDZDLFYRJZSRK-ZHACJKMWSA-N (e)-3-[3-(3-chlorophenyl)-1,2,4-triazol-1-yl]-n-methyl-n-phenylprop-2-enamide Chemical compound C=1C=CC=CC=1N(C)C(=O)\C=C\N(N=1)C=NC=1C1=CC=CC(Cl)=C1 RCDZDLFYRJZSRK-ZHACJKMWSA-N 0.000 claims 2
- DRDQGJCDVFFQMI-UHFFFAOYSA-N 1-(1-benzothiophen-3-ylmethyl)pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1CC1=CSC2=CC=CC=C12 DRDQGJCDVFFQMI-UHFFFAOYSA-N 0.000 claims 1
- FHBLPSBHNPTLLW-UHFFFAOYSA-N 1-(4-cyclohexylphenyl)pyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C1=CC=C(C2CCCCC2)C=C1 FHBLPSBHNPTLLW-UHFFFAOYSA-N 0.000 claims 1
- OSQFPAZNMSSUDP-UHFFFAOYSA-N 1-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]-3-methylpyrrole-2,5-dione Chemical compound O=C1C(C)=CC(=O)N1C1=NC(C=2C=CC(Cl)=CC=2)=CS1 OSQFPAZNMSSUDP-UHFFFAOYSA-N 0.000 claims 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 1
- 210000000214 mouth Anatomy 0.000 claims 1
- UTSKESAKVLVKNU-VAWYXSNFSA-N tert-butyl n-[4-[[(e)-3-[3-(3-chlorophenyl)-1,2,4-triazol-1-yl]prop-2-enoyl]amino]phenyl]carbamate Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1NC(=O)\C=C\N1N=C(C=2C=C(Cl)C=CC=2)N=C1 UTSKESAKVLVKNU-VAWYXSNFSA-N 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 124
- 102000049320 CD36 Human genes 0.000 description 82
- 108010045374 CD36 Antigens Proteins 0.000 description 82
- 101710163595 Chaperone protein DnaK Proteins 0.000 description 38
- 101710178376 Heat shock 70 kDa protein Proteins 0.000 description 38
- 101710152018 Heat shock cognate 70 kDa protein Proteins 0.000 description 38
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
- 239000000203 mixture Substances 0.000 description 21
- 108090000623 proteins and genes Proteins 0.000 description 21
- 238000000684 flow cytometry Methods 0.000 description 18
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 14
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 14
- 230000030833 cell death Effects 0.000 description 13
- 210000000805 cytoplasm Anatomy 0.000 description 13
- 230000035755 proliferation Effects 0.000 description 13
- 102000016955 Erythrocyte Anion Exchange Protein 1 Human genes 0.000 description 12
- 108010014384 Erythrocyte Anion Exchange Protein 1 Proteins 0.000 description 12
- 210000003013 erythroid precursor cell Anatomy 0.000 description 12
- 210000001995 reticulocyte Anatomy 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 11
- 210000003979 eosinophil Anatomy 0.000 description 11
- 239000013612 plasmid Substances 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- 239000013598 vector Substances 0.000 description 11
- 230000001086 cytosolic effect Effects 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 241000700605 Viruses Species 0.000 description 9
- 238000003776 cleavage reaction Methods 0.000 description 9
- 230000007017 scission Effects 0.000 description 9
- 239000002552 dosage form Substances 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 239000002243 precursor Substances 0.000 description 8
- 241000702421 Dependoparvovirus Species 0.000 description 7
- 108010044495 Fetal Hemoglobin Proteins 0.000 description 7
- 108010028165 GATA1 Transcription Factor Proteins 0.000 description 7
- 102000016669 GATA1 Transcription Factor Human genes 0.000 description 7
- 230000000925 erythroid effect Effects 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 230000030147 nuclear export Effects 0.000 description 7
- 241001430294 unidentified retrovirus Species 0.000 description 7
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 101100485279 Drosophila melanogaster emb gene Proteins 0.000 description 5
- 102000003951 Erythropoietin Human genes 0.000 description 5
- 108090000394 Erythropoietin Proteins 0.000 description 5
- 208000007502 anemia Diseases 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 229940105423 erythropoietin Drugs 0.000 description 5
- 210000004700 fetal blood Anatomy 0.000 description 5
- 238000003119 immunoblot Methods 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 5
- 238000007920 subcutaneous administration Methods 0.000 description 5
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 4
- 101100004408 Arabidopsis thaliana BIG gene Proteins 0.000 description 4
- 102100021519 Hemoglobin subunit beta Human genes 0.000 description 4
- 108091005904 Hemoglobin subunit beta Proteins 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000007918 intramuscular administration Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 108090000397 Caspase 3 Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 102100027685 Hemoglobin subunit alpha Human genes 0.000 description 3
- 108091005902 Hemoglobin subunit alpha Proteins 0.000 description 3
- 101001066268 Homo sapiens Erythroid transcription factor Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000000295 complement effect Effects 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000000799 fluorescence microscopy Methods 0.000 description 3
- 235000003642 hunger Nutrition 0.000 description 3
- 238000010348 incorporation Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 210000003924 normoblast Anatomy 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 230000030648 nucleus localization Effects 0.000 description 3
- 239000013600 plasmid vector Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000037351 starvation Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 238000010361 transduction Methods 0.000 description 3
- 230000026683 transduction Effects 0.000 description 3
- 239000013603 viral vector Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 108020005544 Antisense RNA Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 102000003952 Caspase 3 Human genes 0.000 description 2
- 108010041986 DNA Vaccines Proteins 0.000 description 2
- 229940021995 DNA vaccine Drugs 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- YACHGFWEQXFSBS-UHFFFAOYSA-N Leptomycin B Natural products OC(=O)C=C(C)CC(C)C(O)C(C)C(=O)C(C)C=C(C)C=CCC(C)C=C(CC)C=CC1OC(=O)C=CC1C YACHGFWEQXFSBS-UHFFFAOYSA-N 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 108010066154 Nuclear Export Signals Proteins 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 108091028664 Ribonucleotide Proteins 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 239000003184 complementary RNA Substances 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 230000002616 endonucleolytic effect Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 230000009368 gene silencing by RNA Effects 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000011132 hemopoiesis Effects 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- YACHGFWEQXFSBS-XYERBDPFSA-N leptomycin B Chemical compound OC(=O)/C=C(C)/C[C@H](C)[C@@H](O)[C@H](C)C(=O)[C@H](C)/C=C(\C)/C=C/C[C@@H](C)/C=C(/CC)\C=C\[C@@H]1OC(=O)C=C[C@@H]1C YACHGFWEQXFSBS-XYERBDPFSA-N 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000005937 nuclear translocation Effects 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000002336 ribonucleotide Substances 0.000 description 2
- 125000002652 ribonucleotide group Chemical group 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- KXMUNWPEHIUIET-UHFFFAOYSA-N 1-(3-benzoyl-4-methylthiophen-2-yl)pyrrole-2,5-dione Chemical compound C=1C=CC=CC=1C(=O)C=1C(C)=CSC=1N1C(=O)C=CC1=O KXMUNWPEHIUIET-UHFFFAOYSA-N 0.000 description 1
- VAMQLZCXRXXOSK-UHFFFAOYSA-N 1-(4-bromo-2,5-difluorophenyl)pyrrole-2,5-dione Chemical compound C1=C(Br)C(F)=CC(N2C(C=CC2=O)=O)=C1F VAMQLZCXRXXOSK-UHFFFAOYSA-N 0.000 description 1
- YMGYPUVJOUFUGE-UHFFFAOYSA-N 1-[4-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]pyrrole-2,5-dione Chemical compound N1=C(C(F)(F)F)C=CN1C1=CC=C(N2C(C=CC2=O)=O)C=C1 YMGYPUVJOUFUGE-UHFFFAOYSA-N 0.000 description 1
- BAWHYOHVWHQWFQ-UHFFFAOYSA-N 1-naphthalen-1-ylpyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C1=CC=CC2=CC=CC=C12 BAWHYOHVWHQWFQ-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- LDFXTRYMMZGKIC-UPHRSURJSA-N 2-[(z)-2-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]ethenyl]-1,3,4-oxadiazole Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C=3OC=NN=3)C=N2)=C1 LDFXTRYMMZGKIC-UPHRSURJSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- NHPGTSMKZRIWCJ-UHFFFAOYSA-N 4-(4-chlorophenyl)-1,3-thiazole Chemical compound C1=CC(Cl)=CC=C1C1=CSC=N1 NHPGTSMKZRIWCJ-UHFFFAOYSA-N 0.000 description 1
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 108020004491 Antisense DNA Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- LKJQFYUGPNRXAT-CMDGGOBGSA-N ClC=1C=C(C=CC=1)C1=NN(C=N1)/C=C/C(=O)NC1=CC=C(C=C1)NC(O)=O Chemical compound ClC=1C=C(C=CC=1)C1=NN(C=N1)/C=C/C(=O)NC1=CC=C(C=C1)NC(O)=O LKJQFYUGPNRXAT-CMDGGOBGSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241001269524 Dura Species 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 241000713858 Harvey murine sarcoma virus Species 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical class OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 206010065973 Iron Overload Diseases 0.000 description 1
- 108010062228 Karyopherins Proteins 0.000 description 1
- 102000011781 Karyopherins Human genes 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000713869 Moloney murine leukemia virus Species 0.000 description 1
- 241000204795 Muraena helena Species 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 101710199667 Nuclear export protein Proteins 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 241001631646 Papillomaviridae Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- 208000009052 Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 206010038997 Retroviral infections Diseases 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 206010042566 Superinfection Diseases 0.000 description 1
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000035010 Term birth Diseases 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001716 anti-fugal effect Effects 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000003816 antisense DNA Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 235000012255 calcium oxide Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 239000013000 chemical inhibitor Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 230000006743 cytoplasmic accumulation Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000010437 erythropoiesis Effects 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 102000018146 globin Human genes 0.000 description 1
- 108060003196 globin Proteins 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000002743 insertional mutagenesis Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000037041 intracellular level Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 235000014413 iron hydroxide Nutrition 0.000 description 1
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000004942 nuclear accumulation Effects 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000008823 permeabilization Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 150000004713 phosphodiesters Chemical class 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001566 pro-viral effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- KLXKTTGROYBSDM-VOTSOKGWSA-N propan-2-yl (e)-3-[3-(3-chlorophenyl)-1,2,4-triazol-1-yl]prop-2-enoate Chemical compound CC(C)OC(=O)\C=C\N1C=NC(C=2C=C(Cl)C=CC=2)=N1 KLXKTTGROYBSDM-VOTSOKGWSA-N 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 229950010613 selinexor Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 231100001055 skeletal defect Toxicity 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003104 tissue culture media Substances 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000009385 viral infection Effects 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- 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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
- G01N33/5073—Stem cells
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/02—Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/10—Screening for compounds of potential therapeutic value involving cells
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Urology & Nephrology (AREA)
- Molecular Biology (AREA)
- Cell Biology (AREA)
- Diabetes (AREA)
- Food Science & Technology (AREA)
- Analytical Chemistry (AREA)
- Microbiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Developmental Biology & Embryology (AREA)
- Toxicology (AREA)
- Physics & Mathematics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本発明は、ベータ−サラセミアの処置のための方法及び医薬組成物に関する。
成体哺乳動物のHgは、(α/β)2四量体ヘモグロビン(Hb)分子を一緒に形成する2本のαグロビン鎖と2本のβグロビン鎖を含む、多量体タンパク質である。ベータ−サラセミアは、ヘモグロビンのβ鎖の合成の定量的欠乏によって引き起こされる遺伝性血液障害の一群である。この障害を有する個体では、β−グロビン鎖の合成が減少しているか又は存在しない。この疾患の3つの主な形態が以下に記載される:β鎖が産生されない重症型β−サラセミア(β−TM又はβ0−TM)、並びにβ鎖が産生されるが正常な量よりも少ない中間型β−サラセミア及び軽症型β−サラセミア。これらの状態は、重症貧血〜臨床的に無症状の個体に及ぶ異なる表現型を引き起こす。β−TMを有する個体は、通常、人生の最初の2年以内に、重症貧血、成長不良及び幼年期の間の骨格異常を呈する。罹患した子供は、規則的な一生続く輸血を必要とするだろう。中間型β−サラセミアは、重症型β−サラセミアよりも重症度が低く、一時的な輸血を必要とし得る。輸血依存患者は、鉄過剰負荷を発症し、過剰な鉄を取り除くためにキレート療法を必要とするだろう。
本発明は、ベータ−サラセミアの処置のための方法及び医薬組成物に関する。特に、本発明は、特許請求の範囲によって定義される。
本発明は、この欠陥プロセスに介入するように、かつβ−TMに罹患している個体において赤血球成熟を促進又は回復するように設計された方法及び医薬組成物を提供する。β−TM赤血球ではβグロビンが形成されないので、本明細書に記載される方法及び組成物で処置された個体において産生される種類の赤血球は(α/γ)2Hbを含有すること、そして本発明がβ−TM細胞及びβ−TM個体において(α/γ)2Hb赤血球の産生を増大させるための方法及び組成物を提供することに注目されたい。本方法は、細胞質へのHSP70の核外輸送を防止することによってGATA−1の活性を維持することを包含する。したがって、本発明の目的は、GATA−1のタンパク質分解性不活性化を防止することによって重症型β−サラセミア(β−TM)に罹患している被験体における赤血球成熟を回復又は増大させる方法を提供することである。いくつかの実施態様において、防止することは、被験体にXPO1核内輸送体を阻害する化合物を投与することによって達成される。
及びその薬学的に許容し得る塩からなる群より選択される。
又はその薬学的に許容し得る塩からなる群より選択される。
からなる群より選択される。
背景
XPO1の化学阻害剤であるレプトマイシンB(LMB)が赤血球前駆体細胞中のHSP70の核内保持を誘導することを本発明者等の研究室が公表した(Ribeil et al., Nature 2007)。この観察は、XPO1が赤血球前駆体中のHSP70タンパク質の核外輸送に関与し得ることを示唆している。
材料
Obstetrics Unit of Hopital Necker-Enfants Maladesから、母親のインフォームドコンセントを得た後に正常満期産からの臍帯血単位を得た。臍帯血から単離された7日間のIL−6+IL3+SCFで培養したCD34前駆細胞から生成された、CD36+赤血球前駆細胞(Miltenyi CD34 Progenitor Cell Isolation Kit)を、15%BIT 9500(Stem Cell Technologies)を補充したIMDM(Gibco cell culture)中、IL3+SCF+Epoの存在下で培養した。
別個の細胞質フラクションと核タンパク質フラクションを、NE−PER核及び細胞質抽出試薬(Thermo Scientific)を使用して、製造業者のプロトコールに従って、赤血球前駆細胞から抽出した。
使用される抗体は、抗HDACマウスクローン3F3 #05−814(Millipore)、抗HSP70ウサギADI SPA 812(Enzo lifesciences)、及び抗CRM1(XPO1)ウサギ#ST1100(Calbiochem)である。
5.104個の細胞をスライド上にスピンオンし、アセトン固定し、冷1×PBS 1%BSAで30分間水和し、ホルムアルデヒド(Sigma)で15分間、次いで、メタノール(Prolabo)で10分間、室温で処理した。次いで、細胞を、4℃で、1×PBS 0,2%triton X100(Sigma)で10分間透過処理し、洗浄し、そして10%BSA中で30分間インキュベートした。次いで、これらを、1×PBS 1%BSA 0,1%tween(Sigma)で希釈した抗体で連続してインキュベートした。核をDAPIで染色し、スライドを共焦点レーザ顕微鏡(LSM 700 Carl Zeiss)で調べた。
本発明者等は、臍帯血からのCD36+赤血球前駆細胞中のXPO1タンパク質の発現をイムノブロット(図1)及び蛍光顕微鏡法(図2)によって調査した。図1では、培養の3日目(D3)〜6日目(D6)で、XPO1タンパク質は、大部分がCD36+赤血球前駆細胞の細胞質(C)中に存在し、核(N)分画においてはより程度が少ない。図2では、イムノブロッティングによって観察されたXPO1タンパク質の発現が、Epo中の培養の6日目に、透過処理したCD36+赤血球前駆細胞上で共焦点顕微鏡によって確認される。ここで、本発明者等は、CD36+赤血球前駆細胞中のXPO1(ベータインポーチンファミリーの核外輸送タンパク質)の発現を初めて報告する。
図6及び図7のデータは、ベータ−サラセミア患者からのCD36+細胞での2種の異なる実験のものである。図8のデータは、図7の実験からの細胞で遂行された。ベータ−サラセミア赤芽球を、重症型ベータ−サラセミア(β0−TM)を有する成人患者からの末梢血循環CD34+細胞からインビトロで生成した。この研究は、本発明者等の機関の倫理委員会の承認を得て、ヘルシンキ宣言(Helsinky Declaration)に従って遂行した。
本出願を通して、様々な参考文献が、本発明が関わる分野の最先端を記載している。これらの参考文献の開示は、参照によって本開示に組み入れられる。
Claims (14)
- GATA−1のタンパク質分解性不活性化を防止することによって重症型β−サラセミア(β−TM)に罹患している被験体における赤血球成熟を回復又は増大させる方法に用いられる医薬組成物であって、防止することが被験体にXPO1核内輸送体を阻害する化合物を投与することによって達成される方法に用いられるための医薬組成物であって、
XPO1核内輸送体を阻害する化合物を有効成分として含み、
XPO1核内輸送体を阻害する化合物が、以下の化合物:
及びその薬学的に許容し得る塩からなる群より選択される、XPO1核内輸送体を阻害する化合物を有効成分として含む医薬組成物。 - GATA−1のタンパク質分解性不活性化を防止することによって重症型β−サラセミア(β−TM)に罹患している被験体における赤血球成熟を回復又は増大させる方法に用いられる医薬組成物であって、防止することが被験体にXPO1核内輸送体を阻害する化合物を投与することによって達成される方法に用いられるための医薬組成物であって、
XPO1核内輸送体を阻害する化合物を有効成分として含み、
XPO1核内輸送体を阻害する化合物が、(Z)−3−[3−(3−クロロ−フェニル)−[1,2,4]−トリアゾール−1−イル]−アクリル酸エチルエステル;(E)−3−[3−(3−クロロ−フェニル)−[1,2,4]−トリアゾール−1−イル]−アクリル酸エチルエステル;(Z)−3−[3−(3−クロロ−フェニル)−[1,2,4]−トリアゾール−1−イル]−アクリル酸イソプロピルエステル;(E)−3−[3−(3−クロロ−フェニル)−[1,2,4]−トリアゾール−1−イル]−アクリル酸イソプロピルエステル;(Z)−3−[3−(3−クロロ−フェニル)−[1,2,4]−トリアゾール−1−イル]−アクリル酸tert−ブチルエステル;(Z)−3−[3−(3−クロロ−フェニル)−[1,2,4]−トリアゾール−1−イル]−アクリル酸tert−ブチルエステル;(E)−3−[3−(3−クロロ−フェニル)−[1,2,4]−トリアゾール−1−イル]−N−フェニル−アクリルアミド;(E)−N−(2−クロロ−フェニル)−3−[3−(3−クロロ−フェニル)−[1,2,4]−トリアゾール−1−イル]−アクリルアミド;(4−{(E)−3−[3−(3−クロロ−フェニル)−[1,2,4]−トリアゾール−1−イル]−アクリロイルアミノ}−フェニル)−カルバミン酸tert−ブチルエステル;(E)−3−[3−(3−クロロ−フェニル)−[1,2,4]−トリアゾール−1−イル]−N−(4−メトキシ−フェニル)−アクリルアミド;(E)−3−[3−(3−クロロ−フェニル)−[1,2,4]−トリアゾール−1−イル]−N−メチル−N−フェニル−アクリルアミド;(E)−3−[3−(3−クロロ−フェニル)−[1,2,4]−トリアゾール−1−イル]−N−メチル−N−フェニル−アクリルアミド;(E)−N−(4−アミノ−フェニル)−3−[3−(3−クロロ−フェニル)−[1,2,4]−トリアゾール−1−イル]−アクリルアミド及びその薬学的に許容し得る塩からなる群より選択される、XPO1核内輸送体を阻害する化合物を有効成分として含む医薬組成物。 - GATA−1のタンパク質分解性不活性化を防止することによって重症型β−サラセミア(β−TM)に罹患している被験体における赤血球成熟を回復又は増大させる方法に用いられる医薬組成物であって、防止することが被験体にXPO1核内輸送体を阻害する化合物を投与することによって達成される方法に用いられるための医薬組成物であって、
XPO1核内輸送体を阻害する化合物を有効成分として含み、
XPO1核内輸送体を阻害する化合物が、以下の化合物:
及びその薬学的に許容し得る塩からなる群より選択される、XPO1核内輸送体を阻害する化合物を有効成分として含む医薬組成物。 - GATA−1のタンパク質分解性不活性化を防止することによって重症型β−サラセミア(β−TM)に罹患している被験体における赤血球成熟を回復又は増大させる方法に用いられる医薬組成物であって、防止することが被験体にXPO1核内輸送体を阻害する化合物を投与することによって達成される方法に用いられるための医薬組成物であって、
XPO1核内輸送体を阻害する化合物を有効成分として含み、
XPO1核内輸送体を阻害する化合物が、1−(4−メトキシフェニル)−1H−ピロール−2,5−ジオン;1−(4−ブロモ−2,5−ジフルオロフェニル)−1H−ピロール−2,5−ジオン;3−メチル−1−(1−メチル−1H−ピラゾール−3−イル)−1H−ピロール−2,5−ジオン;4−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)−N−(5−メチルイソオキサゾール−3−イル)ベンゼンスルホンアミド;1−(3−ベンゾイル−4−メチルチオフェン−2−イル)−1H−ピロール−2,5−ジオン;1−(4−(3−(トリフルオロメチル)−1H−ピラゾール−1−イル)フェニル)−1H−ピロール−2,5−ジオン;1−(4−(4−クロロフェニル)チアゾール−2−イル)−3−メチル−1H−ピロール−2,5−ジオン;1−(ベンゾ[b]チオフェン−3−イルメチル)−1H−ピロール−2,5−ジオン;1−(3,4−ジメトキシフェネチル)−1H−ピロール−2,5−ジオン;1−(ナフタレン−1−イル)−1H−ピロール−2,5−ジオン;1−(4−シクロヘキシルフェニル)−1H−ピロール−2,5−ジオン;1−(2−ベンゾイルフェニル)−1H−ピロール−2,5−ジオン;1−(4−モルホリノフェニル)−1H−ピロール−2,5−ジオン;1−(4−クロロフェネチル)−1H−ピロール−2,5−ジオン;1−(2−(チオフェン−2−イル)エチル)−1H−ピロール−2,5−ジオン;1−([3,4]メチレンジオキシベンジル)−1H−ピロール−2,5−ジオンアミドからなる群より選択される化合物及びその薬学的に許容し得る塩からなる群より選択される、XPO1核内輸送体を阻害する化合物を有効成分として含む医薬組成物。 - GATA−1のタンパク質分解性不活性化を防止することによって重症型β−サラセミア(β−TM)に罹患している被験体における赤血球成熟を回復又は増大させる方法に用いられる医薬組成物であって、防止することが被験体にXPO1核内輸送体を阻害する化合物を投与することによって達成される方法に用いられるための医薬組成物であって、
XPO1核内輸送体を阻害する化合物を有効成分として含み、
XPO1核内輸送体を阻害する化合物が、以下の化合物:
からなる群より選択される、XPO1核内輸送体を阻害する化合物を有効成分として含む医薬組成物。 - GATA−1のタンパク質分解性不活性化を防止することによって重症型β−サラセミア(β−TM)に罹患している被験体における赤血球成熟を回復又は増大させる方法に用いられる医薬組成物であって、防止することが被験体にXPO1核内輸送体を阻害する化合物を投与することによって達成される方法に用いられるための医薬組成物であって、
XPO1核内輸送体を阻害する化合物を有効成分として含み、
XPO1核内輸送体を阻害する化合物が、以下の式:
を有するKPT−330である、XPO1核内輸送体を阻害する化合物を有効成分として含む医薬組成物。 - GATA−1のタンパク質分解性不活性化を防止することによって重症型β−サラセミア(β−TM)に罹患している被験体における赤血球成熟を回復又は増大させる方法に用いられる医薬組成物であって、防止することが被験体にXPO1核内輸送体を阻害する化合物を投与することによって達成される方法に用いられるための医薬組成物であって、
XPO1核内輸送体を阻害する化合物を有効成分として含み、
XPO1核内輸送体を阻害する化合物が、以下の式:
を有するKPT−276である、XPO1核内輸送体を阻害する化合物を有効成分として含む医薬組成物。 - XPO1核内輸送体を阻害する化合物がXPO1阻害剤である、請求項1〜7のいずれか1項に記載の医薬組成物。
- 必要とする被験体におけるベータ−サラセミアを処置する方法に用いられる医薬組成物であって、被験体に治療有効量のXPO1阻害剤を投与することを含む方法に用いられるための医薬組成物であって、請求項8に記載のXPO1阻害剤を有効成分として含む医薬組成物。
- ベータ−サラセミアに罹患している被験体における赤血球成熟を促進又は回復させるための方法に用いられる医薬組成物であって、被験体に治療有効量のXPO1阻害剤を投与することを含む方法に用いられるための医薬組成物であって、請求項8に記載のXPO1阻害剤を有効成分として含む医薬組成物。
- ベータ−サラセミアに罹患している被験体における(α/γ)2Hb赤血球の産生を増大させるための方法に用いられる医薬組成物であって、被験体に治療有効量のXPO1阻害剤を投与することを含む方法に用いられるための医薬組成物であって、請求項8に記載のXPO1阻害剤を有効成分として含む医薬組成物。
- XPO1核内輸送体を阻害する化合物又はXPO1阻害剤が、XPO1発現の阻害剤である、請求項1〜11のいずれか1項に記載の医薬組成物。
- 遺伝子発現の阻害剤が、siRNA、アンチセンスオリゴヌクレオチド又はリボザイムである、請求項12に記載の医薬組成物。
- ベータ−サラセミアの処置に好適な薬物をスクリーニングするためのインビトロの方法であって、i)候補化合物を準備する工程、ii)XPO1活性又は発現を阻害する能力について候補化合物を試験する工程、及びiii)XPO1活性又は発現を阻害することが可能な候補化合物を選択する工程からなる工程を含む方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13306628.2 | 2013-11-28 | ||
EP13306628 | 2013-11-28 | ||
PCT/EP2014/075980 WO2015079031A1 (en) | 2013-11-28 | 2014-11-28 | Methods and pharmaceutical compositions for the treatment of beta-thalassemias |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2017502929A JP2017502929A (ja) | 2017-01-26 |
JP2017502929A5 JP2017502929A5 (ja) | 2017-12-28 |
JP6527149B2 true JP6527149B2 (ja) | 2019-06-05 |
Family
ID=49713040
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016534904A Expired - Fee Related JP6527149B2 (ja) | 2013-11-28 | 2014-11-28 | ベータ−サラセミアの処置のための方法及び医薬組成物 |
Country Status (5)
Country | Link |
---|---|
US (1) | US9861615B2 (ja) |
EP (1) | EP3074007B1 (ja) |
JP (1) | JP6527149B2 (ja) |
ES (1) | ES2739637T3 (ja) |
WO (1) | WO2015079031A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20220249486A1 (en) * | 2019-06-06 | 2022-08-11 | The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. | Setbp1 and xpo1 inhibitors for the treatment of sickle cell disease and beta-thalassemia |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2791914C (en) * | 2010-03-05 | 2019-01-15 | Karyopharm Therapeutics, Inc. | Nuclear transport modulators and uses thereof |
CN103402359B (zh) * | 2011-01-17 | 2016-08-24 | 卡尔约药物治疗公司 | 含烯烃核运输调节剂及其用途 |
PL2736887T3 (pl) * | 2011-07-29 | 2018-03-30 | Karyopharm Therapeutics, Inc. | Modulatory transportu jądrowego zawierające ugrupowanie hydrazydu i ich zastosowania |
US9428490B2 (en) * | 2011-07-29 | 2016-08-30 | Karyopharm Therapeutics Inc. | Nuclear transport modulators and uses thereof |
WO2013020024A2 (en) * | 2011-08-03 | 2013-02-07 | Karyopharm Therapeutics, Inc. | Maleimide compounds and methods of treatment |
-
2014
- 2014-11-28 ES ES14808905T patent/ES2739637T3/es active Active
- 2014-11-28 WO PCT/EP2014/075980 patent/WO2015079031A1/en active Application Filing
- 2014-11-28 JP JP2016534904A patent/JP6527149B2/ja not_active Expired - Fee Related
- 2014-11-28 US US15/039,230 patent/US9861615B2/en not_active Expired - Fee Related
- 2014-11-28 EP EP14808905.5A patent/EP3074007B1/en not_active Not-in-force
Also Published As
Publication number | Publication date |
---|---|
ES2739637T3 (es) | 2020-02-03 |
WO2015079031A1 (en) | 2015-06-04 |
US9861615B2 (en) | 2018-01-09 |
JP2017502929A (ja) | 2017-01-26 |
US20170020847A1 (en) | 2017-01-26 |
EP3074007A1 (en) | 2016-10-05 |
EP3074007B1 (en) | 2019-07-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
McColl et al. | Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice | |
JP5342834B2 (ja) | 骨髄線維症処置剤 | |
Zhou et al. | Microglial debris is cleared by astrocytes via C4b-facilitated phagocytosis and degraded via RUBICON-dependent noncanonical autophagy in mice | |
EP2679221B1 (en) | Method to enhance tissue regeneration | |
Chavez et al. | Novel therapies for Alport syndrome | |
US11345738B2 (en) | Compounds for treating neurodegenerative proteinopathies | |
US20130267581A1 (en) | Agent for treating myelofibrosis | |
JP2018531046A (ja) | 核酸ベースのtia−1阻害剤 | |
JP2018531046A6 (ja) | 核酸ベースのtia−1阻害剤 | |
US20210317461A1 (en) | Oligonucleotide compositions for targeting ccr2 and csf1r and uses thereof | |
US20190111111A1 (en) | Treatment of Cerebral Cavernous Malformations | |
JP6527149B2 (ja) | ベータ−サラセミアの処置のための方法及び医薬組成物 | |
WO2015174443A1 (ja) | インターロイキン1α(IL-1α)を含有する巨核球分化誘導及び血小板産生促進剤 | |
US9675590B2 (en) | Methods and pharmaceutical compositions for the treatment of myelodysplastic syndromes | |
WO2015035414A1 (en) | Treating neurological disorders | |
EP4051273A1 (en) | Treatment of renal cystic disease | |
US20220143128A1 (en) | Methods for treating traumatic brain injury | |
JPWO2015046574A1 (ja) | 虚血後の再灌流に起因する出血を予防するための薬剤 | |
Yan et al. | Functional engineered exosomes mitigate pathological ischemic retinopathy through a dual strategy of inflammatory microenvironment modulation and angiogenic factor control | |
US20160304881A1 (en) | Ddr1 antagonist or an inhibitor of ddr1 gene expression for use in the prevention or treatment of crescentic glomerulonephritis | |
WO2024059335A1 (en) | Methods of treating age-related and inherited retinal dysfunctions | |
KR20230159847A (ko) | 염증성 또는 활성화된 세포를 표적으로 하고 염증성 상태 및 통증을 치료 또는 개선하기 위한 조성물 및 방법 | |
TW202327566A (zh) | 包含藻褐素及小分子褐藻醣膠之組合物用於製備治療或改善慢性腎病之醫藥品的用途及包含藻褐素、小分子褐藻醣膠及左旋肉鹼之組合物及包含其的醫藥品 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20171117 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20171117 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20180807 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20181106 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190108 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190403 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20190416 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20190509 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6527149 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |