CA2301877A1 - Procede de traitement du cancer - Google Patents
Procede de traitement du cancer Download PDFInfo
- Publication number
- CA2301877A1 CA2301877A1 CA002301877A CA2301877A CA2301877A1 CA 2301877 A1 CA2301877 A1 CA 2301877A1 CA 002301877 A CA002301877 A CA 002301877A CA 2301877 A CA2301877 A CA 2301877A CA 2301877 A1 CA2301877 A1 CA 2301877A1
- Authority
- CA
- Canada
- Prior art keywords
- protein
- geranylgeranyl
- seq
- protein transferase
- compound
- 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.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 135
- 206010028980 Neoplasm Diseases 0.000 title abstract description 31
- 201000011510 cancer Diseases 0.000 title abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 211
- 102000004357 Transferases Human genes 0.000 claims abstract description 148
- 108090000992 Transferases Proteins 0.000 claims abstract description 148
- 150000001450 anions Chemical class 0.000 claims abstract description 102
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 99
- 238000000338 in vitro Methods 0.000 claims abstract description 68
- 238000003556 assay Methods 0.000 claims abstract description 61
- 239000003112 inhibitor Substances 0.000 claims abstract description 55
- 239000003558 transferase inhibitor Substances 0.000 claims abstract description 25
- 241000124008 Mammalia Species 0.000 claims abstract description 21
- 238000001727 in vivo Methods 0.000 claims abstract description 21
- 229940125436 dual inhibitor Drugs 0.000 claims abstract description 18
- 230000000694 effects Effects 0.000 claims abstract description 17
- 229940123468 Transferase inhibitor Drugs 0.000 claims abstract description 16
- 108090000623 proteins and genes Proteins 0.000 claims description 98
- 102000004169 proteins and genes Human genes 0.000 claims description 92
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 72
- -1 dithiophosphate Chemical compound 0.000 claims description 70
- 239000000758 substrate Substances 0.000 claims description 69
- 238000012546 transfer Methods 0.000 claims description 56
- 238000005259 measurement Methods 0.000 claims description 46
- 125000002686 geranylgeranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 45
- 210000004027 cell Anatomy 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 26
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 24
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate 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-N 0.000 claims description 23
- 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 claims description 23
- 229960001456 adenosine triphosphate Drugs 0.000 claims description 23
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 22
- 230000012010 growth Effects 0.000 claims description 22
- 125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 21
- 238000012360 testing method Methods 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 210000002950 fibroblast Anatomy 0.000 claims description 17
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 15
- 235000011180 diphosphates Nutrition 0.000 claims description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 claims description 11
- XKMLYUALXHKNFT-UHFFFAOYSA-N rGTP Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O XKMLYUALXHKNFT-UHFFFAOYSA-N 0.000 claims description 11
- 150000001408 amides Chemical class 0.000 claims description 9
- SUYVUBYJARFZHO-RRKCRQDMSA-N dATP Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-RRKCRQDMSA-N 0.000 claims description 9
- HAAZLUGHYHWQIW-KVQBGUIXSA-N dGTP Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 HAAZLUGHYHWQIW-KVQBGUIXSA-N 0.000 claims description 9
- WKKCYLSCLQVWFD-UHFFFAOYSA-N 1,2-dihydropyrimidin-4-amine Chemical compound N=C1NCNC=C1 WKKCYLSCLQVWFD-UHFFFAOYSA-N 0.000 claims description 8
- MMWCIQZXVOZEGG-XJTPDSDZSA-N D-myo-Inositol 1,4,5-trisphosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@@H](O)[C@@H]1OP(O)(O)=O MMWCIQZXVOZEGG-XJTPDSDZSA-N 0.000 claims description 8
- PGAVKCOVUIYSFO-XVFCMESISA-N UTP Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 PGAVKCOVUIYSFO-XVFCMESISA-N 0.000 claims description 8
- 230000005907 cancer growth Effects 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 8
- 235000019832 sodium triphosphate Nutrition 0.000 claims description 8
- 239000001226 triphosphate Substances 0.000 claims description 8
- UNXRWKVEANCORM-UHFFFAOYSA-I triphosphate(5-) Chemical compound [O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O UNXRWKVEANCORM-UHFFFAOYSA-I 0.000 claims description 8
- PGAVKCOVUIYSFO-UHFFFAOYSA-N uridine-triphosphate Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)OC1N1C(=O)NC(=O)C=C1 PGAVKCOVUIYSFO-UHFFFAOYSA-N 0.000 claims description 8
- OINNEUNVOZHBOX-XBQSVVNOSA-N Geranylgeranyl diphosphate Natural products [P@](=O)(OP(=O)(O)O)(OC/C=C(\CC/C=C(\CC/C=C(\CC/C=C(\C)/C)/C)/C)/C)O OINNEUNVOZHBOX-XBQSVVNOSA-N 0.000 claims description 7
- 229910019142 PO4 Inorganic materials 0.000 claims description 7
- 239000010452 phosphate Substances 0.000 claims description 7
- 238000010348 incorporation Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- PFMUCCYYAAFKTH-YFKPBYRVSA-N Gly-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)CN PFMUCCYYAAFKTH-YFKPBYRVSA-N 0.000 claims description 5
- 239000004471 Glycine Substances 0.000 claims description 5
- BEALYENGMRDLRK-LKEWCRSYSA-N [hydroxy-[[(2s,4r,5r)-4-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]phosphoryl] phosphono hydrogen phosphate Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)C[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 BEALYENGMRDLRK-LKEWCRSYSA-N 0.000 claims description 3
- BJFPYGGTDAYECS-UHFFFAOYSA-N (3-chlorophenyl)methanamine Chemical compound NCC1=CC=CC(Cl)=C1 BJFPYGGTDAYECS-UHFFFAOYSA-N 0.000 claims description 2
- OINNEUNVOZHBOX-QIRCYJPOSA-K 2-trans,6-trans,10-trans-geranylgeranyl diphosphate(3-) Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C(C)=C\COP([O-])(=O)OP([O-])([O-])=O OINNEUNVOZHBOX-QIRCYJPOSA-K 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- ZIHZYWHDESZXNR-UHFFFAOYSA-N 4-[[2-[[4-(3-chlorophenyl)-3-oxopiperazin-1-yl]methyl]imidazol-1-yl]methyl]-2-methoxybenzonitrile 2-methoxy-4-[[2-[[3-oxo-4-[3-(trifluoromethoxy)phenyl]piperazin-1-yl]methyl]imidazol-1-yl]methyl]benzonitrile Chemical compound FC(OC=1C=C(C=CC1)N1C(CN(CC1)CC=1N(C=CN1)CC1=CC(=C(C=C1)C#N)OC)=O)(F)F.ClC=1C=C(C=CC1)N1C(CN(CC1)CC=1N(C=CN1)CC1=CC(=C(C=C1)C#N)OC)=O ZIHZYWHDESZXNR-UHFFFAOYSA-N 0.000 claims description 2
- KNJIXCAYSLDPMD-UHFFFAOYSA-N 4-[[5-[[1-(3-chlorophenyl)-2-oxopyridin-4-yl]methyl]imidazol-1-yl]methyl]-2-methoxybenzonitrile Chemical compound C1=C(C#N)C(OC)=CC(CN2C(=CN=C2)CC2=CC(=O)N(C=3C=C(Cl)C=CC=3)C=C2)=C1 KNJIXCAYSLDPMD-UHFFFAOYSA-N 0.000 claims description 2
- OBMVDAMYNMONNX-UHFFFAOYSA-N 4-[[5-[[4-hydroxy-4-(3-methylphenyl)piperidin-1-yl]methyl]imidazol-1-yl]methyl]benzonitrile Chemical compound CC1=CC=CC(C2(O)CCN(CC=3N(C=NC=3)CC=3C=CC(=CC=3)C#N)CC2)=C1 OBMVDAMYNMONNX-UHFFFAOYSA-N 0.000 claims description 2
- MWGFFPODNXGVSD-UHFFFAOYSA-N IC=1C=C(C=CC1)N1C(CN(CC1)CC=1N(C=CN1)CC1=CC=C(C=C1)C#N)=O.CC=1C=C(C=CC1)N1C(CN(CC1)CC=1N(C=CN1)CC1=CC=C(C=C1)C#N)=O Chemical compound IC=1C=C(C=CC1)N1C(CN(CC1)CC=1N(C=CN1)CC1=CC=C(C=C1)C#N)=O.CC=1C=C(C=CC1)N1C(CN(CC1)CC=1N(C=CN1)CC1=CC=C(C=C1)C#N)=O MWGFFPODNXGVSD-UHFFFAOYSA-N 0.000 claims description 2
- DINDWXWEUFDMSN-TYLGTTGKSA-N O=C(c1ccccc1)c1ccc(NCc2cncn2Cc2ccc(cc2)C#N)cc1.CC[C@H]1CCN(C[C@@H]2CCCN2C(=O)Cc2cncn2Cc2ccc(cc2)C#N)[C@@H]1C(O)=O Chemical compound O=C(c1ccccc1)c1ccc(NCc2cncn2Cc2ccc(cc2)C#N)cc1.CC[C@H]1CCN(C[C@@H]2CCCN2C(=O)Cc2cncn2Cc2ccc(cc2)C#N)[C@@H]1C(O)=O DINDWXWEUFDMSN-TYLGTTGKSA-N 0.000 claims description 2
- GDAQDTCKYVKPPC-PMERELPUSA-N benzyl n-[(3-chlorophenyl)methyl]-n-[(2s)-2-[[3-[(4-cyanophenyl)methyl]imidazol-4-yl]methylamino]-4-methylsulfonylbutyl]carbamate Chemical compound C([C@H](CCS(=O)(=O)C)NCC=1N(C=NC=1)CC=1C=CC(=CC=1)C#N)N(C(=O)OCC=1C=CC=CC=1)CC1=CC=CC(Cl)=C1 GDAQDTCKYVKPPC-PMERELPUSA-N 0.000 claims description 2
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- NZRNYTPQNGERDW-WJOKGBTCSA-N n-[[(3s)-1-benzhydrylpiperidin-3-yl]methyl]-n-[2-[3-[(4-cyanophenyl)methyl]-2-methylimidazol-4-yl]ethyl]acetamide Chemical compound C([C@@H]1CN(CCC1)C(C=1C=CC=CC=1)C=1C=CC=CC=1)N(C(=O)C)CCC1=CN=C(C)N1CC1=CC=C(C#N)C=C1 NZRNYTPQNGERDW-WJOKGBTCSA-N 0.000 claims description 2
- RZCIEJXAILMSQK-JXOAFFINSA-N TTP Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 RZCIEJXAILMSQK-JXOAFFINSA-N 0.000 claims 5
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 3
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 claims 1
- HEERXEXCUKUJPR-FSRHOLMTSA-N N1C=NC(=C1)CCC(=O)N1[C@@H](CCC1)CN(CC(=O)N[C@@H](CCSC)C(=O)O)CC1=C(C=CC=C1)OC.N1C=NC(=C1)CCC(=O)N1[C@@H](CCC1)CN(CC(=O)N[C@@H](CCSC)C(=O)O)CC1=C(C=CC=C1)OC Chemical compound N1C=NC(=C1)CCC(=O)N1[C@@H](CCC1)CN(CC(=O)N[C@@H](CCSC)C(=O)O)CC1=C(C=CC=C1)OC.N1C=NC(=C1)CCC(=O)N1[C@@H](CCC1)CN(CC(=O)N[C@@H](CCSC)C(=O)O)CC1=C(C=CC=C1)OC HEERXEXCUKUJPR-FSRHOLMTSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 103
- 125000003118 aryl group Chemical group 0.000 description 94
- 239000000243 solution Substances 0.000 description 82
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 79
- 125000000623 heterocyclic group Chemical group 0.000 description 79
- 125000000217 alkyl group Chemical group 0.000 description 78
- 229910052739 hydrogen Inorganic materials 0.000 description 75
- 239000001257 hydrogen Substances 0.000 description 70
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 102200160920 rs35304565 Human genes 0.000 description 55
- 235000018102 proteins Nutrition 0.000 description 47
- 239000000047 product Substances 0.000 description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 239000000543 intermediate Substances 0.000 description 42
- 239000000203 mixture Substances 0.000 description 42
- 238000002360 preparation method Methods 0.000 description 42
- 150000002431 hydrogen Chemical class 0.000 description 41
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 description 36
- 125000000753 cycloalkyl group Chemical group 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 125000003107 substituted aryl group Chemical group 0.000 description 32
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 30
- 125000003342 alkenyl group Chemical group 0.000 description 28
- 108010014186 ras Proteins Proteins 0.000 description 28
- 239000002904 solvent Substances 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 25
- 102000016914 ras Proteins Human genes 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 239000007787 solid Substances 0.000 description 24
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 23
- 125000001424 substituent group Chemical group 0.000 description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 21
- 150000001299 aldehydes Chemical class 0.000 description 20
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000012267 brine Substances 0.000 description 19
- 230000005764 inhibitory process Effects 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 17
- 235000001014 amino acid Nutrition 0.000 description 17
- 229940024606 amino acid Drugs 0.000 description 17
- 229910052736 halogen Inorganic materials 0.000 description 17
- 238000000746 purification Methods 0.000 description 17
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 150000002367 halogens Chemical class 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 102000004190 Enzymes Human genes 0.000 description 15
- 108090000790 Enzymes Proteins 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 15
- 239000003814 drug Substances 0.000 description 15
- 229940088598 enzyme Drugs 0.000 description 15
- 239000003921 oil Substances 0.000 description 15
- 235000019198 oils Nutrition 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 150000001412 amines Chemical class 0.000 description 14
- 150000001413 amino acids Chemical class 0.000 description 14
- 229910052799 carbon Inorganic materials 0.000 description 14
- 238000011282 treatment Methods 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- 229910052801 chlorine Inorganic materials 0.000 description 13
- 229910052731 fluorine Inorganic materials 0.000 description 13
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 125000004122 cyclic group Chemical group 0.000 description 12
- 125000005842 heteroatom Chemical group 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 102220389089 c.33G>T Human genes 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 125000002883 imidazolyl group Chemical group 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- VWFJDQUYCIWHTN-YFVJMOTDSA-N 2-trans,6-trans-farnesyl diphosphate Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CO[P@](O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-YFVJMOTDSA-N 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 238000005804 alkylation reaction Methods 0.000 description 10
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 10
- 229910052760 oxygen Inorganic materials 0.000 description 10
- 125000004076 pyridyl group Chemical group 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 9
- 125000000304 alkynyl group Chemical group 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 231100000252 nontoxic Toxicity 0.000 description 9
- 230000003000 nontoxic effect Effects 0.000 description 9
- 238000005932 reductive alkylation reaction Methods 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 102000006495 integrins Human genes 0.000 description 8
- 108010044426 integrins Proteins 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 230000013823 prenylation Effects 0.000 description 8
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
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- 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
- G01N33/5011—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 for testing antineoplastic activity
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- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
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- A—HUMAN NECESSITIES
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- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- 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
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K38/005—Enzyme inhibitors
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/99—Enzyme inactivation by chemical treatment
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Microbiology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- General Engineering & Computer Science (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- General Physics & Mathematics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Cell Biology (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Food Science & Technology (AREA)
- Toxicology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Enzymes And Modification Thereof (AREA)
Abstract
L'invention concerne un procédé pour inhiber les prényl-protéine-transférases et traiter le cancer, qui consiste à administrer à un mammifère un inhibiteur de prényl-protéine-transférase constituant un inhibiteur efficace in vivo de la géranylgéranyl-protéine-transférase de type I (GGTase-I). L'invention concerne aussi un procédé permettant d'inhiber la farnésyl-protéine-transférase et la géranylgéranyl-protéine-transférase de type I en administrant un composé qui est un double inhibiteur pour ces deux prényl-protéine-transférases. L'invention concerne en outre un procédé permettant d'identifier le composé susmentionné, qui consiste en un essai inhibiteur modifié comprenant un anion modulateur capable de modifier l'activité in vitro des inhibiteurs de prényl-protéine-transférase de manière à prévoir l'activité in vivo de ces inhibiteurs, moyennant quoi il est possible d'identifier aisément les composés possédant ladite activité in vivo.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US5734097P | 1997-08-27 | 1997-08-27 | |
US60/057,340 | 1997-08-27 | ||
GBGB9724331.5A GB9724331D0 (en) | 1997-11-18 | 1997-11-18 | A method of treating cancer |
GB9724331.5 | 1997-11-18 | ||
PCT/US1998/017697 WO1999010523A1 (fr) | 1997-08-27 | 1998-08-26 | Procede de traitement du cancer |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2301877A1 true CA2301877A1 (fr) | 1999-03-04 |
Family
ID=26312617
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002301877A Abandoned CA2301877A1 (fr) | 1997-08-27 | 1998-08-26 | Procede de traitement du cancer |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1009854A1 (fr) |
JP (1) | JP2001518281A (fr) |
AU (1) | AU9205898A (fr) |
CA (1) | CA2301877A1 (fr) |
WO (1) | WO1999010523A1 (fr) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9809889D0 (en) | 1998-05-11 | 1998-07-08 | Univ Strathclyde | Prevention of restenosis |
US6849599B2 (en) | 2000-03-08 | 2005-02-01 | Rhode Island Hospital | Combination drug therapy |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5185248A (en) * | 1990-05-08 | 1993-02-09 | E. R. Squibb & Sons, Inc. | Farnesyl-protein transferase assay for identifying compounds that block neoplastic transformation |
-
1998
- 1998-08-26 EP EP98944537A patent/EP1009854A1/fr not_active Withdrawn
- 1998-08-26 AU AU92058/98A patent/AU9205898A/en not_active Abandoned
- 1998-08-26 CA CA002301877A patent/CA2301877A1/fr not_active Abandoned
- 1998-08-26 JP JP2000507831A patent/JP2001518281A/ja active Pending
- 1998-08-26 WO PCT/US1998/017697 patent/WO1999010523A1/fr not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
EP1009854A1 (fr) | 2000-06-21 |
JP2001518281A (ja) | 2001-10-16 |
WO1999010523A1 (fr) | 1999-03-04 |
AU9205898A (en) | 1999-03-16 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Discontinued |