TWI518086B - ＰＩ３－激酶／ｍＴＯＲ雙重抑制劑 - Google Patents
ＰＩ３－激酶／ｍＴＯＲ雙重抑制劑 Download PDFInfo
- Publication number
- TWI518086B TWI518086B TW100148428A TW100148428A TWI518086B TW I518086 B TWI518086 B TW I518086B TW 100148428 A TW100148428 A TW 100148428A TW 100148428 A TW100148428 A TW 100148428A TW I518086 B TWI518086 B TW I518086B
- Authority
- TW
- Taiwan
- Prior art keywords
- cancer
- compound
- methyl
- imidazo
- quinolin
- Prior art date
Links
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 title description 17
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 title description 17
- 101150097381 Mtor gene Proteins 0.000 title 1
- 229940125436 dual inhibitor Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 114
- 206010028980 Neoplasm Diseases 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 23
- 201000011510 cancer Diseases 0.000 claims description 18
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 14
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 7
- 206010017758 gastric cancer Diseases 0.000 claims description 7
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 7
- 201000011549 stomach cancer Diseases 0.000 claims description 7
- ACCFLVVUVBJNGT-AWEZNQCLSA-N 8-[5-(2-hydroxypropan-2-yl)pyridin-3-yl]-1-[(2s)-2-methoxypropyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound CN1C(=O)N(C[C@H](C)OC)C(C2=C3)=C1C=NC2=CC=C3C1=CN=CC(C(C)(C)O)=C1 ACCFLVVUVBJNGT-AWEZNQCLSA-N 0.000 claims description 6
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
- 206010038389 Renal cancer Diseases 0.000 claims description 5
- 208000005017 glioblastoma Diseases 0.000 claims description 5
- 201000010982 kidney cancer Diseases 0.000 claims description 5
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 4
- 201000010536 head and neck cancer Diseases 0.000 claims description 4
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 206010014733 Endometrial cancer Diseases 0.000 claims description 3
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010039491 Sarcoma Diseases 0.000 claims description 3
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 201000007455 central nervous system cancer Diseases 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000003394 haemopoietic effect Effects 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 201000000849 skin cancer Diseases 0.000 claims description 3
- 201000002510 thyroid cancer Diseases 0.000 claims description 3
- MOWFRTVNIAZOCA-UHFFFAOYSA-N 3-methyl-1h-imidazo[4,5-c]quinolin-2-one Chemical compound C1=CC=CC2=C(NC(N3C)=O)C3=CN=C21 MOWFRTVNIAZOCA-UHFFFAOYSA-N 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 210000003563 lymphoid tissue Anatomy 0.000 claims 2
- 208000016847 malignant urinary system neoplasm Diseases 0.000 claims 2
- 230000000241 respiratory effect Effects 0.000 claims 2
- 201000004435 urinary system cancer Diseases 0.000 claims 2
- 230000029087 digestion Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 64
- 210000004027 cell Anatomy 0.000 description 51
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 44
- 238000006243 chemical reaction Methods 0.000 description 43
- 239000000203 mixture Substances 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- 239000007787 solid Substances 0.000 description 29
- 235000019439 ethyl acetate Nutrition 0.000 description 28
- 239000000243 solution Substances 0.000 description 26
- 238000004458 analytical method Methods 0.000 description 25
- 238000000034 method Methods 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 230000005764 inhibitory process Effects 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 21
- 208000032839 leukemia Diseases 0.000 description 21
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 241001465754 Metazoa Species 0.000 description 18
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 17
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 17
- 108091007960 PI3Ks Proteins 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 16
- 238000003556 assay Methods 0.000 description 15
- 239000013078 crystal Substances 0.000 description 15
- 239000000523 sample Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- 108091000080 Phosphotransferase Proteins 0.000 description 14
- 102000020233 phosphotransferase Human genes 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 13
- 101000605639 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 description 13
- 102100038332 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Human genes 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000002609 medium Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 229940088598 enzyme Drugs 0.000 description 9
- 239000012091 fetal bovine serum Substances 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000012458 free base Substances 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 8
- -1 Pyridine compound Chemical class 0.000 description 8
- 241000282472 Canis lupus familiaris Species 0.000 description 7
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 7
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 7
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 7
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 231100000673 dose–response relationship Toxicity 0.000 description 7
- 229950007919 egtazic acid Drugs 0.000 description 7
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 7
- 239000005090 green fluorescent protein Substances 0.000 description 7
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 7
- 230000005855 radiation Effects 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229910016523 CuKa Inorganic materials 0.000 description 6
- 102000005768 DNA-Activated Protein Kinase Human genes 0.000 description 6
- 108010006124 DNA-Activated Protein Kinase Proteins 0.000 description 6
- 239000007995 HEPES buffer Substances 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000011324 bead Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 230000026731 phosphorylation Effects 0.000 description 6
- 238000006366 phosphorylation reaction Methods 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 230000003389 potentiating effect Effects 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 238000013207 serial dilution Methods 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 5
- 241000238631 Hexapoda Species 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 238000002441 X-ray diffraction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 235000011180 diphosphates Nutrition 0.000 description 5
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 229940126409 proton pump inhibitor Drugs 0.000 description 5
- 102200085639 rs104886003 Human genes 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- SJVSNQJOFQKUGC-QMMMGPOBSA-N 8-bromo-1-[(2s)-2-methoxypropyl]-3h-imidazo[4,5-c]quinolin-2-one Chemical compound C1=C(Br)C=C2C(N(C(N3)=O)C[C@H](C)OC)=C3C=NC2=C1 SJVSNQJOFQKUGC-QMMMGPOBSA-N 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 102100022466 Eukaryotic translation initiation factor 4E-binding protein 1 Human genes 0.000 description 4
- 108050000946 Eukaryotic translation initiation factor 4E-binding protein 1 Proteins 0.000 description 4
- 102000005720 Glutathione transferase Human genes 0.000 description 4
- 108010070675 Glutathione transferase Proteins 0.000 description 4
- 241000699660 Mus musculus Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 239000012823 PI3K/mTOR inhibitor Substances 0.000 description 4
- 239000004793 Polystyrene Substances 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- 238000003016 alphascreen Methods 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 4
- 239000001177 diphosphate Substances 0.000 description 4
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229960001484 edetic acid Drugs 0.000 description 4
- 238000009585 enzyme analysis Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 210000000265 leukocyte Anatomy 0.000 description 4
- 239000006166 lysate Substances 0.000 description 4
- 238000011580 nude mouse model Methods 0.000 description 4
- 150000003904 phospholipids Chemical class 0.000 description 4
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- BTIWBTYSCGIKRO-UHFFFAOYSA-N 2-(5-bromopyridin-3-yl)propan-2-ol Chemical compound CC(C)(O)C1=CN=CC(Br)=C1 BTIWBTYSCGIKRO-UHFFFAOYSA-N 0.000 description 3
- 241000208340 Araliaceae Species 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 3
- 235000003140 Panax quinquefolius Nutrition 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- 206010036790 Productive cough Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 3
- 239000012636 effector Substances 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 235000008434 ginseng Nutrition 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 3
- 229960000367 inositol Drugs 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000002821 scintillation proximity assay Methods 0.000 description 3
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 3
- 208000024794 sputum Diseases 0.000 description 3
- 210000003802 sputum Anatomy 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- HDXPVDSGCDOOFU-WCCKRBBISA-N (2s)-2-methoxypropan-1-amine;hydrochloride Chemical compound Cl.CO[C@@H](C)CN HDXPVDSGCDOOFU-WCCKRBBISA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 2
- IBXMKLPFLZYRQZ-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 IBXMKLPFLZYRQZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- GQFLADCQCJHNDE-QMMMGPOBSA-N 6-bromo-4-[[(2s)-2-methoxypropyl]amino]quinoline-3-carboxylic acid Chemical compound C1=C(Br)C=C2C(NC[C@H](C)OC)=C(C(O)=O)C=NC2=C1 GQFLADCQCJHNDE-QMMMGPOBSA-N 0.000 description 2
- 108010013238 70-kDa Ribosomal Protein S6 Kinases Proteins 0.000 description 2
- LQXNSMGAPOCMCP-VIFPVBQESA-N 8-bromo-1-[(2s)-2-methoxypropyl]-3-methylimidazo[4,5-c]quinolin-2-one Chemical compound C1=C(Br)C=C2C(N(C(N3C)=O)C[C@H](C)OC)=C3C=NC2=C1 LQXNSMGAPOCMCP-VIFPVBQESA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 2
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 2
- DHCLVCXQIBBOPH-UHFFFAOYSA-N Glycerol 2-phosphate Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 2
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000623857 Homo sapiens Serine/threonine-protein kinase mTOR Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229930193140 Neomycin Natural products 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 102000018120 Recombinases Human genes 0.000 description 2
- 108010091086 Recombinases Proteins 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 239000002518 antifoaming agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000011717 athymic nude mouse Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 2
- 238000004820 blood count Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000012937 correction Methods 0.000 description 2
- 235000001671 coumarin Nutrition 0.000 description 2
- 229960000956 coumarin Drugs 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 2
- 239000013024 dilution buffer Substances 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 238000001952 enzyme assay Methods 0.000 description 2
- 239000003797 essential amino acid Substances 0.000 description 2
- 235000020776 essential amino acid Nutrition 0.000 description 2
- PCPIANOJERKFJI-UHFFFAOYSA-N ethyl 5-bromopyridine-3-carboxylate Chemical compound CCOC(=O)C1=CN=CC(Br)=C1 PCPIANOJERKFJI-UHFFFAOYSA-N 0.000 description 2
- JUUNCVJNWNFJIO-JTQLQIEISA-N ethyl 6-bromo-4-[[(2s)-2-methoxypropyl]amino]quinoline-3-carboxylate Chemical compound C1=CC(Br)=CC2=C(NC[C@H](C)OC)C(C(=O)OCC)=CN=C21 JUUNCVJNWNFJIO-JTQLQIEISA-N 0.000 description 2
- YGMLKBFPHVLHGT-UHFFFAOYSA-N ethyl 6-bromo-4-chloroquinoline-3-carboxylate Chemical compound C1=CC(Br)=CC2=C(Cl)C(C(=O)OCC)=CN=C21 YGMLKBFPHVLHGT-UHFFFAOYSA-N 0.000 description 2
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 210000001161 mammalian embryo Anatomy 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 229960004927 neomycin Drugs 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-M nicotinate Chemical compound [O-]C(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-M 0.000 description 2
- ZPIRTVJRHUMMOI-UHFFFAOYSA-N octoxybenzene Chemical compound CCCCCCCCOC1=CC=CC=C1 ZPIRTVJRHUMMOI-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- 239000011535 reaction buffer Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 229940054269 sodium pyruvate Drugs 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- IQYPSFAWXDKDBA-UHFFFAOYSA-N 1,3-dihydroimidazo[4,5-c]quinolin-2-one Chemical compound C1=CC=CC2=C(NC(=O)N3)C3=CN=C21 IQYPSFAWXDKDBA-UHFFFAOYSA-N 0.000 description 1
- BLJDNLNGOZOVNJ-UHFFFAOYSA-N 1-methyl-3h-imidazo[4,5-c]quinolin-2-one Chemical compound C1=CC=C2C(N(C(N3)=O)C)=C3C=NC2=C1 BLJDNLNGOZOVNJ-UHFFFAOYSA-N 0.000 description 1
- ODWNBAWYDSWOAF-UHFFFAOYSA-N 2,4,4-trimethylpentan-2-yloxybenzene Chemical compound CC(C)(C)CC(C)(C)OC1=CC=CC=C1 ODWNBAWYDSWOAF-UHFFFAOYSA-N 0.000 description 1
- GXVUZYLYWKWJIM-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanamine Chemical compound NCCOCCN GXVUZYLYWKWJIM-UHFFFAOYSA-N 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- JJMQRJKPLUACSO-UHFFFAOYSA-N 3-(4-iodophenyl)-2-(4-nitrophenyl)-5-phenyl-1,3-dihydrotetrazol-3-ium;chloride Chemical compound [Cl-].C1=CC([N+](=O)[O-])=CC=C1N1N(C=2C=CC(I)=CC=2)[NH2+]C(C=2C=CC=CC=2)=N1 JJMQRJKPLUACSO-UHFFFAOYSA-N 0.000 description 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 1
- FQIUCPGDKPXSLL-UHFFFAOYSA-N 5-bromopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CN=CC(Br)=C1 FQIUCPGDKPXSLL-UHFFFAOYSA-N 0.000 description 1
- 239000012099 Alexa Fluor family Substances 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 238000003734 CellTiter-Glo Luminescent Cell Viability Assay Methods 0.000 description 1
- 229910052684 Cerium Inorganic materials 0.000 description 1
- 229940122644 Chymotrypsin inhibitor Drugs 0.000 description 1
- 101710137926 Chymotrypsin inhibitor Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- SRUWWOSWHXIIIA-UKPGNTDSSA-N Cyanoginosin Chemical compound N1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](C)[C@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C(=C)N(C)C(=O)CC[C@H](C(O)=O)N(C)C(=O)[C@@H](C)[C@@H]1\C=C\C(\C)=C\[C@H](C)[C@@H](O)CC1=CC=CC=C1 SRUWWOSWHXIIIA-UKPGNTDSSA-N 0.000 description 1
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 1
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 125000002842 L-seryl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])O[H] 0.000 description 1
- 241000254158 Lampyridae Species 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- 102000006830 Luminescent Proteins Human genes 0.000 description 1
- 108010047357 Luminescent Proteins Proteins 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 1
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
- 108010035196 Mechanistic Target of Rapamycin Complex 1 Proteins 0.000 description 1
- 102000008135 Mechanistic Target of Rapamycin Complex 1 Human genes 0.000 description 1
- 108010034057 Mechanistic Target of Rapamycin Complex 2 Proteins 0.000 description 1
- 102000009308 Mechanistic Target of Rapamycin Complex 2 Human genes 0.000 description 1
- 239000012828 PI3K inhibitor Substances 0.000 description 1
- 101150037263 PIP2 gene Proteins 0.000 description 1
- 101710093328 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 description 1
- 102000011755 Phosphoglycerate Kinase Human genes 0.000 description 1
- 206010035603 Pleural mesothelioma Diseases 0.000 description 1
- 206010051950 Pleural sarcoma Diseases 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 101100262439 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) UBA2 gene Proteins 0.000 description 1
- 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FKMJXALNHKIDOD-LBPRGKRZSA-N TAMe Chemical compound NC(=N)NCCC[C@@H](C(=O)OC)NS(=O)(=O)C1=CC=C(C)C=C1 FKMJXALNHKIDOD-LBPRGKRZSA-N 0.000 description 1
- 101001099217 Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8) Triosephosphate isomerase Proteins 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- MWKWDHRMEHIBTP-BYPYZUCNSA-N [(2S)-2-methoxypropyl]carbamic acid Chemical compound CO[C@@H](C)CNC(O)=O MWKWDHRMEHIBTP-BYPYZUCNSA-N 0.000 description 1
- CFVBFMMHFBHNPZ-UHFFFAOYSA-N [Na].[V] Chemical compound [Na].[V] CFVBFMMHFBHNPZ-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 238000002820 assay format Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 125000005340 bisphosphate group Chemical group 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000008235 cell cycle pathway Effects 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 1
- 239000012916 chromogenic reagent Substances 0.000 description 1
- 239000003541 chymotrypsin inhibitor Substances 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 230000005757 colony formation Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- DXPIZCZNFUTPEI-UHFFFAOYSA-O diphenylphosphanium;azide Chemical compound [N-]=[N+]=[N-].C=1C=CC=CC=1[PH2+]C1=CC=CC=C1 DXPIZCZNFUTPEI-UHFFFAOYSA-O 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 108010007093 dispase Proteins 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 1
- IVZIOBTVAJBBAS-UHFFFAOYSA-N ethyl 6-bromo-4-oxo-1h-quinoline-3-carboxylate Chemical compound C1=C(Br)C=C2C(=O)C(C(=O)OCC)=CNC2=C1 IVZIOBTVAJBBAS-UHFFFAOYSA-N 0.000 description 1
- BUBWTSJXUHKBBX-UHFFFAOYSA-N ethyl acetate;sodium Chemical compound [Na].CCOC(C)=O BUBWTSJXUHKBBX-UHFFFAOYSA-N 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000009246 food effect Effects 0.000 description 1
- 235000021471 food effect Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000036397 gastrointestinal physiology Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 102000057995 human PIK3CA Human genes 0.000 description 1
- 238000013415 human tumor xenograft model Methods 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- HOPZBJPSUKPLDT-UHFFFAOYSA-N imidazo[4,5-h]quinolin-2-one Chemical class C1=CN=C2C3=NC(=O)N=C3C=CC2=C1 HOPZBJPSUKPLDT-UHFFFAOYSA-N 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- SORXVYYPMXPIFD-UHFFFAOYSA-N iron palladium Chemical compound [Fe].[Pd] SORXVYYPMXPIFD-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 229940116298 l- malic acid Drugs 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 235000015263 low fat diet Nutrition 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 239000011565 manganese chloride Substances 0.000 description 1
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 229940099607 manganese chloride Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- IZXGZAJMDLJLMF-UHFFFAOYSA-N methylaminomethanol Chemical compound CNCO IZXGZAJMDLJLMF-UHFFFAOYSA-N 0.000 description 1
- 108010067094 microcystin Proteins 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- QNDVLZJODHBUFM-WFXQOWMNSA-N okadaic acid Chemical compound C([C@H](O1)[C@H](C)/C=C/[C@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)[C@@H](O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(OCCCC4)O3)C)O2)C(C)=C[C@]21O[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]2O QNDVLZJODHBUFM-WFXQOWMNSA-N 0.000 description 1
- VEFJHAYOIAAXEU-UHFFFAOYSA-N okadaic acid Natural products CC(CC(O)C1OC2CCC3(CCC(O3)C=CC(C)C4CC(=CC5(OC(CC(C)(O)C(=O)O)CCC5O)O4)C)OC2C(O)C1C)C6OC7(CCCCO7)CCC6C VEFJHAYOIAAXEU-UHFFFAOYSA-N 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229940012957 plasmin Drugs 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- YNJCFDAODGKHAV-LURJTMIESA-N tert-butyl n-[(2s)-2-hydroxypropyl]carbamate Chemical compound C[C@H](O)CNC(=O)OC(C)(C)C YNJCFDAODGKHAV-LURJTMIESA-N 0.000 description 1
- CHDRLVXWOMPHDM-ZETCQYMHSA-N tert-butyl n-[(2s)-2-methoxypropyl]carbamate Chemical compound CO[C@@H](C)CNC(=O)OC(C)(C)C CHDRLVXWOMPHDM-ZETCQYMHSA-N 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 201000005990 thymic dysplasia Diseases 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 230000003612 virological effect 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
- A61K31/435—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
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161432958P | 2011-01-14 | 2011-01-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201307343A TW201307343A (zh) | 2013-02-16 |
| TWI518086B true TWI518086B (zh) | 2016-01-21 |
Family
ID=45531593
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW100148428A TWI518086B (zh) | 2011-01-14 | 2011-12-23 | ＰＩ３－激酶／ｍＴＯＲ雙重抑制劑 |
Country Status (39)
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JO3003B1 (ar) | 2011-01-14 | 2016-09-05 | Lilly Co Eli | مركب أيميدازو [4، 5 -c ] كينولين-2- واحد واستخدامه كمثبط كيناز PI3/mtor |
| US9050345B2 (en) | 2013-03-11 | 2015-06-09 | Bristol-Myers Squibb Company | Pyrrolotriazines as potassium ion channel inhibitors |
| US20160264570A1 (en) * | 2013-11-15 | 2016-09-15 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Serv | Method of blocking transmission of malarial parasite |
| TWI609687B (zh) | 2015-04-14 | 2018-01-01 | 美國禮來大藥廠 | 平滑肌肉瘤之標靶性治療 |
| TW201703769A (zh) | 2015-05-08 | 2017-02-01 | 美國禮來大藥廠 | 用於癌症的組合療法 |
| GB201516504D0 (en) * | 2015-09-17 | 2015-11-04 | Astrazeneca Ab | Imadazo(4,5-c)quinolin-2-one Compounds and their use in treating cancer |
| HK1254687A1 (zh) * | 2015-12-15 | 2019-07-26 | Eli Lilly And Company | 用於癌症的联合疗法 |
| US10722484B2 (en) | 2016-03-09 | 2020-07-28 | K-Gen, Inc. | Methods of cancer treatment |
| WO2017180385A1 (en) * | 2016-04-12 | 2017-10-19 | Eli Lilly And Company | Combination therapy with notch and pi3k/mtor inhibitors for use in treating cancer |
| ES2881801T3 (es) * | 2016-04-12 | 2021-11-30 | Lilly Co Eli | Terapia de combinación con inhibidores de Notch y CDK4/6 para su uso en el tratamiento de cáncer de pulmón |
| MA45025A (fr) | 2016-05-20 | 2019-03-27 | Lilly Co Eli | Traitement d'association utilisant des inhibiteurs de notch et de pd-1 ou pd-l1 |
| WO2018017410A1 (en) | 2016-07-22 | 2018-01-25 | Eli Lilly And Company | Combination therapy of abemaciclib and a pi3 kinase/mtor dual inhibitor for use in the treatment of breast cancer |
| WO2018063873A1 (en) | 2016-09-27 | 2018-04-05 | Eli Lilly And Company | Combination therapy of abemaciclib and a pi3 kinase/mtor dual inhibitor for use in the treatment of pancreatic cancer |
| US11376259B2 (en) | 2016-10-12 | 2022-07-05 | Eli Lilly And Company | Targeted treatment of mature T-cell lymphoma |
| IL268349B2 (en) | 2017-02-17 | 2024-08-01 | Hutchinson Fred Cancer Res | Combination therapies for treatment of bcma-related cancers and autoimmune disorders |
| SG11202003427XA (en) | 2017-11-06 | 2020-05-28 | Juno Therapeutics Inc | Combination of a cell therapy and a gamma secretase inhibitor |
| US10596165B2 (en) | 2018-02-12 | 2020-03-24 | resTORbio, Inc. | Combination therapies |
| CN110386932A (zh) | 2018-04-20 | 2019-10-29 | 艾科思莱德制药公司 | 用于抗肿瘤疗法中的双重atm和dna-pk抑制剂 |
| IL314362A (en) | 2018-06-15 | 2024-09-01 | Janssen Pharmaceutica Nv | Rapamycin analogs and their uses |
| WO2020081329A1 (en) * | 2018-10-18 | 2020-04-23 | Camp4 Therapeutics Corporation | Methods and compositions for modulating pcsk9 and angptl3 expression |
| KR20220128345A (ko) | 2019-12-05 | 2022-09-20 | 아나쿠리아 테라퓨틱스, 인코포레이티드 | 라파마이신 유사체 및 이의 용도 |
| ES2974742T3 (es) * | 2020-09-21 | 2024-07-01 | Wei Zhong | Compuestos de 1-(3,3-difluoropiperidin-4-il)-imidazo[4,5-c]quinolin-2-ona sustituidos con capacidad de penetración en la barrera hematoencefálica |
| EP3992191A1 (en) | 2020-11-03 | 2022-05-04 | Deutsches Krebsforschungszentrum | Imidazo[4,5-c]quinoline compounds and their use as atm kinase inhibitors |
| MX2024007790A (es) | 2021-12-22 | 2024-09-06 | Camp4 Therapeutics Corp | Modulación de la transcripción génica utilizando oligonucleótidos antisentido dirigidos a arn reguladores. |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0211649D0 (en) | 2002-05-21 | 2002-07-03 | Novartis Ag | Organic compounds |
| AR046845A1 (es) * | 2003-11-21 | 2005-12-28 | Novartis Ag | Derivados de 1h-imidazo[4,5-c]quinolina para tratamiento de enfermedades dependientes de las proteino-quinasas |
| DE602004014969D1 (de) | 2003-11-21 | 2008-08-21 | Novartis Ag | 1h-imidazochinolinderivate als proteinkinaseinhibitoren |
| CA2598656A1 (en) * | 2005-02-23 | 2006-08-31 | Coley Pharmaceutical Group, Inc. | Hydroxyalkyl substituted imidazoquinoline compounds and methods |
| GB0510390D0 (en) * | 2005-05-20 | 2005-06-29 | Novartis Ag | Organic compounds |
| KR20080083270A (ko) | 2005-11-04 | 2008-09-17 | 콜레이 파마시티컬 그룹, 인코포레이티드 | 하이드록시 및 알콕시 치환된 1에이치 이미다조퀴놀린 및방법 |
| WO2007106854A2 (en) | 2006-03-15 | 2007-09-20 | Coley Pharmaceutical Group, Inc. | Hydroxy and alkoxy substituted 1h-imidazonaphthyridines and methods |
| WO2010038165A1 (en) | 2008-09-30 | 2010-04-08 | Pfizer Inc. | Imidazo[1,5]naphthyridine compounds, their pharmaceutical use and compositions |
| CN102803259A (zh) * | 2009-06-04 | 2012-11-28 | 诺瓦提斯公司 | 用于治疗增殖性疾病的1H-咪唑并[4,5-c]喹啉酮化合物 |
| NZ596487A (en) | 2009-06-04 | 2012-11-30 | Novartis Ag | 1H-IMIDAZO[4,5-c]QUINOLINONE DERIVATIVES AND THE USE THEREOF AS PI3K INHIBITORS |
| AU2009349135A1 (en) * | 2009-06-30 | 2012-02-16 | Piramal Enterprises Limited | Imidazo [4,5-c]quinoline derivatives and their use in the treatment of tumors and/or inflammation |
| JP2014504286A (ja) * | 2010-12-06 | 2014-02-20 | ピラマル エンタープライジーズ リミテッド | 置換イミダゾキノリン誘導体 |
| JO3003B1 (ar) | 2011-01-14 | 2016-09-05 | Lilly Co Eli | مركب أيميدازو [4، 5 -c ] كينولين-2- واحد واستخدامه كمثبط كيناز PI3/mtor |
-
2011
- 2011-12-20 JO JOP/2011/0389A patent/JO3003B1/ar active
- 2011-12-22 AR ARP110104894A patent/AR084551A1/es unknown
- 2011-12-23 TW TW100148428A patent/TWI518086B/zh not_active IP Right Cessation
-
2012
- 2012-01-11 PE PE2013001553A patent/PE20140864A1/es active IP Right Grant
- 2012-01-11 CA CA2824760A patent/CA2824760C/en not_active Expired - Fee Related
- 2012-01-11 EP EP12701207.8A patent/EP2663564B1/en active Active
- 2012-01-11 RS RS20150095A patent/RS53828B1/sr unknown
- 2012-01-11 DK DK12701207.8T patent/DK2663564T3/en active
- 2012-01-11 SI SI201230117T patent/SI2663564T1/sl unknown
- 2012-01-11 JP JP2013549509A patent/JP5891247B2/ja not_active Expired - Fee Related
- 2012-01-11 SG SG2013047311A patent/SG191744A1/en unknown
- 2012-01-11 EA EA201390823A patent/EA022163B1/ru not_active IP Right Cessation
- 2012-01-11 HR HRP20150135AT patent/HRP20150135T1/hr unknown
- 2012-01-11 KR KR1020137018235A patent/KR101561360B1/ko not_active Expired - Fee Related
- 2012-01-11 ES ES12701207.8T patent/ES2531891T3/es active Active
- 2012-01-11 MY MYPI2013701219A patent/MY164705A/en unknown
- 2012-01-11 WO PCT/US2012/020897 patent/WO2012097039A1/en not_active Ceased
- 2012-01-11 US US13/347,886 patent/US8440829B2/en not_active Expired - Fee Related
- 2012-01-11 CN CN201280005256.0A patent/CN103282364B/zh not_active Expired - Fee Related
- 2012-01-11 MX MX2013008185A patent/MX2013008185A/es active IP Right Grant
- 2012-01-11 AU AU2012205619A patent/AU2012205619B2/en not_active Ceased
- 2012-01-11 PH PH1/2013/501493A patent/PH12013501493A1/en unknown
- 2012-01-11 ME MEP-2015-14A patent/ME02019B/me unknown
- 2012-01-11 BR BR112013017672A patent/BR112013017672A2/pt not_active Application Discontinuation
- 2012-01-11 PL PL12701207T patent/PL2663564T3/pl unknown
- 2012-01-11 HU HUE12701207A patent/HUE024426T2/en unknown
- 2012-01-11 PT PT127012078T patent/PT2663564E/pt unknown
- 2012-11-01 UA UAA201308519A patent/UA109921C2/ru unknown
-
2013
- 2013-04-16 US US13/863,411 patent/US8658668B2/en not_active Expired - Fee Related
- 2013-06-03 TN TNP2013000237A patent/TN2013000237A1/fr unknown
- 2013-06-14 CR CR20130289A patent/CR20130289A/es unknown
- 2013-06-24 IL IL227165A patent/IL227165A/en active IP Right Grant
- 2013-06-25 ZA ZA2013/04757A patent/ZA201304757B/en unknown
- 2013-07-01 DO DO2013000158A patent/DOP2013000158A/es unknown
- 2013-07-09 CL CL2013002005A patent/CL2013002005A1/es unknown
- 2013-07-11 GT GT201300180A patent/GT201300180A/es unknown
- 2013-07-12 SV SV2013004496A patent/SV2013004496A/es unknown
- 2013-07-12 EC ECSP13012764 patent/ECSP13012764A/es unknown
- 2013-07-25 CO CO13176485A patent/CO6731133A2/es unknown
-
2015
- 2015-01-30 CY CY20151100096T patent/CY1116007T1/el unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI518086B (zh) | ＰＩ３－激酶／ｍＴＯＲ雙重抑制劑 | |
| JP6701088B2 (ja) | Ｐｉ３ｋ−ガンマ媒介障害の治療で使用するための複素環式化合物 | |
| KR20220006139A (ko) | Stat 분해제 및 이의 용도 | |
| CN109689641B (zh) | 一种取代的2-氢-吡唑衍生物的晶型、盐型及其制备方法 | |
| CN116783180A (zh) | 用于降解ikzf2或ikzf4的三环配体 | |
| TW201706270A (zh) | 作為吲哚胺２，３-二加氧酶和／或色氨酸２，３-二加氧酶抑制劑之新穎之５或８-取代之咪唑並［１，５－ａ］吡啶 | |
| US11945799B2 (en) | 4-ethynylpyridine derivatives useful as GCN2 inhibitors | |
| CN112189009B (zh) | 作为tcr-nck相互作用的抑制剂的色烯衍生物 | |
| WO2025049821A1 (en) | Stat6 degraders and uses thereof | |
| TW202408538A (zh) | Stat降解劑及其用途 | |
| JP2013530250A (ja) | 二環式ピリミジン化合物 | |
| JP6073480B2 (ja) | ＰＩ３Ｋおよび／またはｍＴＯＲ阻害剤 | |
| HK1188454B (en) | Imidazo [4, 5 -c]quinolin- 2 -one compound and its use as pi3 kinase / mtor dual inhibitor | |
| NZ611541B2 (en) | Imidazo[4,5-c]quinolin-2-one compound and its use as pi3 kinase / mtor dual inhibitor | |
| HK1183486A1 (zh) | 三环类pi3k和/或mtor抑制剂 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Annulment or lapse of patent due to non-payment of fees |