CA2301857A1

CA2301857A1 - Procede pour le traitement du cancer

Procede pour le traitement du cancer Download PDF

Info

Publication number: CA2301857A1
Authority: CA; Canada
Prior art keywords: protein; protein transferase; farnesyl; geranylgeranyl; cells
Prior art date: 1997-08-27
Legal status : Abandoned

Application number

CA002301857A

Other languages

English (en)

Inventor

Anne L. Burkhardt

Pearl S. Huang

Kenneth S. Koblan

Nancy E. Kohl

Robert B. Lobell

Carolyn A. Buser-Doepner

Current Assignee

Merck and Co Inc

Original Assignee

Individual

Priority date

1997-08-27

Filing date

1998-08-26

Publication date

1999-03-04

1998-04-06 Priority claimed from GBGB9807361.2A external-priority patent/GB9807361D0/en

1998-08-26 Application filed by Individual filed Critical Individual

1999-03-04 Publication of CA2301857A1 publication Critical patent/CA2301857A1/fr

Status Abandoned legal-status Critical Current

Links

238000000034 method Methods 0.000 title claims abstract description 118
206010028980 Neoplasm Diseases 0.000 title claims abstract description 32
201000011510 cancer Diseases 0.000 title claims abstract description 20
150000001875 compounds Chemical class 0.000 claims abstract description 200
108090000623 proteins and genes Proteins 0.000 claims abstract description 188
102000004169 proteins and genes Human genes 0.000 claims abstract description 184
102000004357 Transferases Human genes 0.000 claims abstract description 174
108090000992 Transferases Proteins 0.000 claims abstract description 174
239000000758 substrate Substances 0.000 claims abstract description 83
230000002401 inhibitory effect Effects 0.000 claims abstract description 65
239000003112 inhibitor Substances 0.000 claims abstract description 59
238000012545 processing Methods 0.000 claims abstract description 45
230000001413 cellular effect Effects 0.000 claims abstract description 25
238000001727 in vivo Methods 0.000 claims abstract description 19
239000003558 transferase inhibitor Substances 0.000 claims abstract description 17
241000124008 Mammalia Species 0.000 claims abstract description 16
229940123468 Transferase inhibitor Drugs 0.000 claims abstract description 13
230000005907 cancer growth Effects 0.000 claims abstract description 9
235000018102 proteins Nutrition 0.000 claims description 181
-1 dithiophosphate Chemical compound 0.000 claims description 68
238000003556 assay Methods 0.000 claims description 64
239000000203 mixture Substances 0.000 claims description 55
108090000765 processed proteins & peptides Proteins 0.000 claims description 41
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 36
108010014186 ras Proteins Proteins 0.000 claims description 33
238000012546 transfer Methods 0.000 claims description 31
238000012360 testing method Methods 0.000 claims description 29
230000005764 inhibitory process Effects 0.000 claims description 28
238000000338 in vitro Methods 0.000 claims description 27
150000003839 salts Chemical class 0.000 claims description 26
150000001450 anions Chemical class 0.000 claims description 23
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 23
235000001014 amino acid Nutrition 0.000 claims description 20
238000011534 incubation Methods 0.000 claims description 20
239000006166 lysate Substances 0.000 claims description 18
150000001413 amino acids Chemical class 0.000 claims description 17
238000005259 measurement Methods 0.000 claims description 16
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 15
239000006228 supernatant Substances 0.000 claims description 14
NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 14
101000595993 Phyllomedusa sauvagei Phylloseptin-S1 Proteins 0.000 claims description 13
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 11
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 11
229960001456 adenosine triphosphate Drugs 0.000 claims description 11
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101100420081 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) rps-0 gene Proteins 0.000 claims description 9
150000001408 amides Chemical class 0.000 claims description 9
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 8
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 7
XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 7
235000011180 diphosphates Nutrition 0.000 claims description 7
230000002934 lysing effect Effects 0.000 claims description 7
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 7
101710113436 GTPase KRas Proteins 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 6
239000004471 Glycine Substances 0.000 claims description 5
235000018417 cysteine Nutrition 0.000 claims description 5
XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 5
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 5
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 5
238000001962 electrophoresis Methods 0.000 claims description 5
230000002621 immunoprecipitating effect Effects 0.000 claims description 5
WKKCYLSCLQVWFD-UHFFFAOYSA-N 1,2-dihydropyrimidin-4-amine Chemical compound N=C1NCNC=C1 WKKCYLSCLQVWFD-UHFFFAOYSA-N 0.000 claims description 4
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 4
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 4
235000019832 sodium triphosphate Nutrition 0.000 claims description 4
239000001226 triphosphate Substances 0.000 claims description 4
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 4
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 4
238000001262 western blot Methods 0.000 claims description 4
FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 3
230000010261 cell growth Effects 0.000 claims description 3
229930182817 methionine Natural products 0.000 claims description 3
238000001556 precipitation Methods 0.000 claims description 3
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
DBHQZLQBOHLAJT-UHFFFAOYSA-N 4-[[5-[[4-(3-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl]imidazol-1-yl]methyl]benzonitrile Chemical compound C1CC(O)(C=2C=C(Cl)C=CC=2)CCN1CC1=CN=CN1CC1=CC=C(C#N)C=C1 DBHQZLQBOHLAJT-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
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
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
101710203837 Replication-associated protein Proteins 0.000 claims 7
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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 2
BJFPYGGTDAYECS-UHFFFAOYSA-N (3-chlorophenyl)methanamine Chemical compound NCC1=CC=CC(Cl)=C1 BJFPYGGTDAYECS-UHFFFAOYSA-N 0.000 claims 1
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 1
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 1
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229940125436 dual inhibitor Drugs 0.000 abstract description 4
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