Hydroxamic acid-based bisubstrate analog inhibitors of Ras farnesyl protein transferase

Journal of Medicinal Chemistry

Volumn 39, Issue 21, 1996, Pages 4197-4210

  Patel, Dinesh V ^a,b   Young, Marian G ^a   Robinson, Simon P ^a,c   Hunihan, Lisa ^a   Dean, Brenda J ^a   Gordon, Eric M ^a,b  

^a BRISTOL MYERS SQUIBB   (United States)

^b Veraicor Inc   (United States)

^c BASF Bioresearch Corporation   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HYDROXAMIC ACID DERIVATIVE; ONCOPROTEIN; PROTEIN FARNESYLTRANSFERASE; PROTEIN FARNESYLTRANSFERASE INHIBITOR;

ANIMAL CELL; ARTICLE; DRUG ACTIVITY; DRUG DESIGN; DRUG SCREENING; DRUG SYNTHESIS; ENZYME INHIBITION; NONHUMAN; ONCOGENE RAS; STRUCTURE ACTIVITY RELATION;

3T3 CELLS; ALKYL AND ARYL TRANSFERASES; ANIMALS; AUTORADIOGRAPHY; DNA; ELECTROPHORESIS, POLYACRYLAMIDE GEL; ENZYME INHIBITORS; GENES, RAS; HYDROXAMIC ACIDS; MICE; MOLECULAR WEIGHT; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSFECTION; TRANSFERASES;

EID: 0029796715     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960190h     Document Type: Article

References (79)

1. (a) Hunter, T. Cooperation between Oncogenes. Cell 1991, 64, 249-270.
2. (b) Liang, P.; Averboukh, L.; Zhu, W.; Pardee, A. B. Ras activation of genes: Mob-1 as a model. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 8323-8327.
3. (a) Barbacid, M. Ras genes. Annu. Rev. Biochem. 1987, 56, 779-827.
4. (b) Stacey, D. W.; Tsai, M.-H.; Yu, C.-L.; Smith, J. K. Critical Role of Cellular ras Proteins in Proliferative Signal Transduction. Cold Spring Harbor Symposia on Quantitative Biology 1988, LIII, 871-881.
5. (c) Gibbs, J. B.; Marshall, M. S. The ras oncogene - an important regulatory element in lower eucaryotic organisms. Microbiol. Rev. 1989, 53, 171-185.
6. (a) Bartek, J.; Bartkova, J.; Vojtesek, B.; Staskova, Z.; Lukas, J.; Rejthar, A.; Kovarik, J.; Midgley, C. A.; Gannon, J. V.; Lane, D. P. Aberrant expression of the p53 oncoprotein is a common feature of a wide spectrum of human maignancies. Oncogene. 1991, 6, 1699-1703.
7. (b) Bos, J. L. Ras oncogenes in human cancer: a review. Cancer Res. 1989, 49, 4682-4689.
8. (a) Gibbs, J. B. Ras C-Terminal Processing Enzymes- New Drug Targets? Cell 1991, 65, 1-4.
9. (b) Der, C. J.; Cox, A. D. Isoprenoid Modification and Plasma Membrane Association: Critical Factors for Ras Oncogenicity. Cancer Cells 1991, 3, 331-340.
10. ras protein: biological amd biochemical significance of the cysteine nearest the carboxy terminus. EMBO J. 1984, 3, 2581-2585.
11. (b) Lowy, D. R.; Willumsen, B. M. New clue to ras lipid glue. Nature (London) 1989, 341, 384-385.
12. (c) Downward, J. Regulatory mechanisms for ras Proteins. BioEssays 1992, 14, 177-184.
13. (a) Casey, P. J.; Solski, P. A.; Der, C. J.; Buss, J. E. p21ras is modified by a farnesyl isoprenoid. Proc. Natl, Acad. Sci. U.S.A. 1989, 86, 8323-8327.
14. (b) Rilling, H. C.; Breunger, E.; Epstein, W. W.; Crain, P. F. Prenylated Proteins: The Structure of the Isoprenoid Group. Science 1990, 247, 318-322.
15. (c) Hoffman, M. Playing Tag With Membrane Proteins. Science 1991, 254, 650-651.
16. (d) Khosravi-Far, R.; Cox, A. D.; Kato, K.; Der, C. J. Protein Prenylation: Key to Ras Function and Cancer Intervention? Cell Growth Differ. 1992, 3, 461-469.
17. (e) Cox, A. D.; Der, C. J. Protein prenylation: more than just glue? Curr. Opin. in Cell Biol. 1992, 4, 1008-1016.
18. (f) Marshall, C. J. Protein Prenylation: A Mediator of Protein-Protein Interactions. Science 1993, 259, 1865-1866.
19. ras protein farnesyl transferase. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 732-736.
20. (b) Moores, S. L.; Schaber, M. D.; Mosser, S. D.; Rands, E.; O'Hara, M. B.; Garsky, V. M.; Marshall, M. S.; Pompliano, D. L.; Gibbs, J. B. Sequence Dependence of Protein Isoprenylation J. Biol. Chem. 1991, 266, 14603-14610.
21. (c) Nigg, E. A.; Kitten, G. T.; Vorburger, K. Targeting lamin proteins to the nuclear envelope: the role of CaaX box modifications. Biochem. Soc. Trans. 1991, 20, 500-504.
22. (a) Ashby, M. N.; King, D. S.; Rine, J. Endoproteolytic processing of a farnesylated peptide in vitro. Proc. Natl. Acad. Sci. U.S.A., 1992, 89, 4613-4617.
23. (b) Ma, Y-T.; Rando, R. R. A microsomal endoprotease that specifically cleaves isoprenylated peptides. Proc. Natl. Acad. Sci. U.S.A., 1992, 89, 6275-6279.
24. (a) Stephenson, R. C.; Clarke, S. Identification of a C-terminal protein carboxyl methyltransferase in rat liver membranes utilizing a synthetic farnesyl cysteine containing peptide substrate. J. Biol. Chem. 1990, 265, 16248-16254.
25. (b) Volker, C.; Miller, R. A.; Stock, J. B. S-Farnesylcysteine methyltransferase in bovine brain. METHODS: A Companion to Methods in Enzymology 1990, 1, 283-287.
26. (c) Volker, C.; Miller, R. A.; McCleary, W. R.; Rao, A.; Poenie, M.; Backer, J. M.; Stock, J. B. Effects of farnesylcysteine analogs on protein carboxyl methylation and signal transduction. J. Biol. Chem. 1991, 266, 21515-21522.
27. (d) Tan, E. W.; P-Sala, D.; Rando, R. R. Heteroatom requirements for substrate recognition by GTP-binding protein methyltransferase. J. Am. Chem. Soc. 1991, 113, 6299-6300.
28. (e) P-Sala, D.; Gilbert, B. A.; Tan, E. W.; Rando, R. R. Prenylated protein methyltransferases do not distinguish between famesylated and geranylgeranylated substrates. Biochem. J. 1992, 284, 835-840.
29. (f) Shi, Y.-Q.; Rando, R. R. Kinetic mechanism of isoprenylated protein methyltransferase. J. Biol. Chem. 1992, 267, 9547-9551.
30. (g) Gilbert, B. A.; Tan, E. W.; P-Sala, D.; Rando, R. R. Structure-activity studies on the retinal rod outer segment isoprenylated protein methyltransferase. J. Amer. Chem. Soc. 1992, 114, 3966-3973.
31. K-ras(B). EMBO J. 1991, 10, 641-646.
32. ras to the plasma membrane. Cell 1990, 63, 133-139.
33. (b) Hancock, J. F.; Cadwallader, K.; Paterson, H.; Marshall, C. J. A CAAX or a CAAL motif and a second signal are sufficient for plasma membrane trageting of ras proteins. EMBO J. 1991, 10, 4033-4039.
34. (a) Clarke, S. Protein isoprenylation and methylation at carboxylterminal cysteine residues. Annu. Rev. Biochem. 1992, 61, 355-386.
35. (b) Cox, A. D.; Der, C. J. Protein prenylation: more than just glue? Curr. Opin. Cell. Biol. 1992, 4, 1008-1016..
36. (a) Manne, V.; Roberts, D.; Tobin, A.; O'Rourke, E.; De Virgilio, M.; Meyers, C.; Ahmed, N.; Kurz, B.; Resh, M.; Kung, H.-F.; Barbacid, M. Identification and preliminary characterization of protein-cysteine farnesyltransferase. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 7541-7545.
37. (b) Schaber, M. D.; O'Hara, M. B.; Garsky, V. M.; Mosser, S. D.; Bergstrom, J. D.; Moores, S. L.; Marshall, M. S.; Friedman, P. A.; Dixon, R. A. F.; Gibbs, J. B. Polyisoprenylation of Ras inVitro by a Farnesyl-Protein Transferase. J. Biol. Chem. 1990, 265, 14701-14704.
38. (c) Reiss, Y.; Seabra, M. C.; Goldstein, J. L.; Brown, M. S. Purification of ras Farnesyl:Protein Transferase. METHODS: A Companion to Methods in Enzymology 1990, 1, 241-245.
39. Gibbs, J. B.; Oliff, A.; Kohl, N. E. Farnesyl transferase inhibitors: Ras research yields a potential cancer therapeutic. Cell 1994, 77, 175-178.
40. ras Farnesyl Protein Transferase by Cys-AAX Tetrapeptides. Cell 1990, 62, 81-88.
41. ras protein farnesyltransferase. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 732-736.
42. (c) Goldstein, J. L.; Brown, M. S.; Stradley, S. J.; Reiss, Y.; Gierasch, L. M. Nonfarnesylated Tetrapeptide Inhibitors of Protein Farnesyltransferase. J. Biol. Chem. 1991, 266, 15575-15578.
43. (a) Pompliano, D. L.; Rands, E.; Schaber, M. D.; Mosser, S. D.; Anthony, N. J.; Gibbs, J. B. Steady-State Kinetic Mechanism of Ras Farnesyl:protein Transferase. Biochemistry 1992, 31, 3800-3807.
44. (b) Singh, S. B.; Zink, D. L.; Liesch, J. M.; Goetz, M. A., Jenkins, R. G.; Nallin-Olmstead, M.; Silverman, K. C.; Bills, G. F.; Mosley, R. T.; Gibbs, J. B.; Albers-Schonberg, G.; Lingham, R. B. Isolation and Structure of Chaetomellic Acids A and B from Chaetomella acutiseta: Farnesyl Pyrophosphate Mimic Inhibitors of Ras Farnesyl-Protein Transferase. Tetrahedron 1993, 49, 5917-5926.
45. (c) Manne, V.; Ricca, C. S.; Gullo Brown, J.; Tuomari, A. V.; Yan, N.; Patel, D. V.; Schmidt, R.; Lynch, M. J.; Ciosek, C. P., Jr.; Carboni, J. M.; Robinson, S.; Gordon, E. M.; Barbacid, M.; Seizinger, B. R.; Biller, S. A. Ras farnesylation as a target for novel antitumor agents: Potent and selective farnesyl diphosphate analog inhibitors of farnesyl transferase. Drug. Dev. Res. 1995, 34, 121-137.
46. (a) Kohl, N. E.; Mosser, S. D.; deSolms, S. J.; Giuliani, E. A.; Pompliano, D. L.; Graham, S. L.; Smith, R. L.; Scolnick, E. M.; Oliff, A.; Gibbs, J. B., Selective Inhibition of ras- Dependent Transformation by a Farnesyltransferase Inhibitor. Science 1993, 260, 1934-1937.
47. (b) James, G. L.; Goldstein, J. L.; Brown, M. S.; Rawson, T. E.; Somers, T. C.; McDowell, R. S.; Crowley, C. W.; Lucas, B. K.; Levinson, A. D.; Marsters, J. C. Jr. Benzodiazepine Peptidomimetics: Potent Inhibitors of Ras Farnesylation in Animal Cells. Science 1993, 260, 1937-1942.
48. (c) Graham, S. L.; deSolms, S. J.; Guiliani, E. A.; Kihl, N. E.; Mosser, S. D.; Oliff, A. I.; Pompliano, D. L.; Rands, E.; Breslin, M. J.; Deana, A. A.; Garsky, V. M.; Scholz, T. H.; Gibbs, J. B.; Smith, R. L. Pseudopeptide Inhibitors of Ras Farnesyl-Protein Transferase. J. Med. Chem. 1994, 37, 725-732.
49. (d) Kohl, N. E.; Wilson, F. R.; Mosser, S. D.; Giuliani, J. E.; deSolms, S. J.; Conner, M. W.; Anthony, N. J.; Holtz, W. J.; R. P., G.; Lee, T.-J.; Smith, R. L.; Graham, S. L.; Hartman, G. D.; Gibbs, J. B.; Oliff, A. Protein Farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 9141-9145.
50. (e) Leftheris, K.; Kline, T.; Natarajan, S.; DeVirgilio, M. K.; Cho, Y. H.; Pluscec, J.; Ricca, C.; Robinson, S.; Seizinger, B. R.; Manne, V.; Meyers, C. A. Bioorg. Med. Chem. Lett. 1994, 4, 887-892.
51. (f) Wai, J. S.; Bamberger, D. L.; Fisher, T. E.; Graham, S. L.; Smith, R. L.; Gibbs, J. B.; Mosser, S. D.; Oliff, A. I.; Pompliano, D. L.; Rands, E.; Kohl, N. E. Synthesis and Biological Activity of Ras Farnesyl Protein Transferase Inhibitors. Tetrapeptide Analogs with Amino Methyl and Carbon Linkages. Bioorg. Med. Chem. 1994, 2, 939-947.
52. (g) Marsters, J. J. C.; McDowell, R. S.; Reynolds, M. E.; Oare, D. A.; Somers, T. C.; Stanley, M. S.; Rawson, T. E.; Struble, M. E.; Burdick, D. J.; Chan, K. S.; Duarte, C. M.; Paris, K. J.; Tom, J. Y. K.; Wan, D. T.; Xue, Y.; Burnier, J. P. Benzodiazepine Peptidomimetic Inhibitors of Farnesyltransferase. Biog. and Med. Chem. 1994, 2, 949-957.
53. (h) Vogt, A.; Qian, Y.; Blaskovich, M. A.; Possum, R. D.; Hamilton, A. D.; Sebti, S. M. A Non-peptide Mimetic of Ras-CAAX: Selective Inhibition of Farnesyltransferase and Ras Processing. J. Biol. Chem. 1995, 270, 660-664.
54. (i) Hunt, J. T.; Lee, V. G.; Leftheris, K.; Seizinger, B.; Carboni, J.; Mabus, J.; Ricca, C.; Yan, N.; Manne, V. Potent, cell active, non-thiol tetrapeptide inhibitors of farnesyltransferase. J. Med. Chem. 1996, 39, 353-358.
55. (a) Bhide, R. S.; Patel, D. V.; Patel, M. M.; Robinson, S. P.; Hunihan, L. W.; Gordon, E. M. Rational design of potent carboxylic acid based bisubstrate inhibitors of ras farnesyl protein transferase. Bioorg. Med. Chem. Lett. 1994, 4, 2107-2112.
56. (b) Patel, D. V.; Gordon, E. M.; Schmidt, R. J.; Weller, H. N.; Young, M. G.; Zahler, R.; Barbacid, M.; Carboni, J. M.; Gullo-Brown, J. L.; Hunihan, L.; Ricca, C.; Robinson, S.; Seizinger, B. R.; Tuomari, V. A.; Yan, N.; Manne, V. Phosphinyl Acid-based Bisubstrate Analog Inhibitors of Ras Farnesyl Protein Transferase. J. Med. Chem. 1995, 38, 435-442.
57. (c) Manne, V.; Yan N.; Carboni, J. M.; Tuomari, A. V.; Ricca, C. S.; Gullo-Brown, J.; Andahazy, M. L.; Schmidt, R. J.; Patel, D. V.; Zahler, R.; Der, C. J.; Cox, A. D.; Weinmann, R.; Hunt, J. T.; Barbacid, M.; Seizinger, B. R. Bisubstrate Inhibitors of Farensyltransferase: A novel class of specific inhibitors of ras transformed cells. Oncogene 1995, 10, 1763-1779.
58. (d) Patel, D. V.; Patel, M. M.; Robinson, S.; Gordon, E. M. Phenol based tripeptide inhibitors of ras farnesyl protein transferase. Bioorg. Med. Chem. Lett. 1994, 4, 1883-1888.
59. (a) Epstein, W. W.; Lever, D. C.; Rilling, H. C. Prenylated proteins: Synthesis of geranylgeranylcysteine and identification of this thioether amino acid as a component of proteins in CHO cells. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 7352-7354.
60. (b) Seabra, M. C.; Reiss, Y.; Casey, P. J.; Brown, M. S.; Goldstein, J.L., Protein Farnesyltransferase and Geranyltransferase Share a Common α Subunit. Cell 1991, 65, 429-434.
61. (c) Casey, P. J.; Thissen, J. A.; Moomaw, J. F. Enzymatic modification of proteins with a geranylgeranyl isoprenoid. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 8631-8635.
62. (d) Yokoyoma, K.; Goodwin, G. W.; Ghomashchi, F.; Glomset, J. A.; Gelb, M. H. A protein geranylgeranyltransferase from bovine brain: Implications for protein prenylation specificity. Proc. Natl. Acad. Sci., 1991, 88, 5302-5306.
63. (e) Kinsella, B. T.; Erdman, R. A.; Maltese, W. A. Posttranslational modification of Ha-ras p21 by farnesyl versus geranylgeranyl isoprenoids is determined by the COOH-terminal amino acid. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 8934-8938.
64. (f) Moomaw, J. F.; Casey, P. J. Mammalian Protein Geranylgeranyltransferase: subunit composition and metal requirements. J. Biol. Chem. 1992, 267, 17438-17443.
65. Gavras, H.; Gavras, I. Angiotensin Converting Enzyme Inhibitors. Properties and Side Effects. Hypertension 1988, 11 (3), Suppl. 11, 37-41.
66. (a) Petrillo, E. W., Jr.; Ondetti, M. A. Angiotensin-Converting Enzyme Inhibitors: Medicinal Chemistry and Biological Actions. Med. Res. Rev. 1982, 2, 1-41.
67. (b) Nishino, N.; Powers J. C. Peptide hydroxamic acids as inhibitors of thermolysin. Biochemistry 1978, 17, 2846-2850.
68. (c) Miller, M. J. Syntheses and therapeutic potential of hydroxamic acid based siderophores and analogues. Chem. Rev. 1989, 89, 1563-1579.
69. H-ras Farnesyltransferase. J. Biol. Chem. 1991, 266, 10672- 10677.
70. Initially, an alternate method for preparation of N-methyl hydroxamic ether intermediate 3 was investigated. Unfortunately, alkylation of 36 was incomplete (<65%) and gave only moderate yields of 3 (<45%) under a variety of reaction conditions, alongwith O- and N-alkylated side products 37 and 38 respectively. equation presented
71. (a) Ramasamy, K.; Olsen, R. K.; Emery, T. N-Methylation of O-Benzyl-N-α-(alkoxycarbonyl)-α-aminoacid hydroxamate derivatives. J. Org. Chem. 1981, 46, 5438-5441.
72. (b) Sharma, S. K.; Miller, M. J.; Payne, S. M. Spermexatin and Spermaxatol: New synthetic Spermidine based siderophore analogues. J. Med. Chem. 1989, 32, 357-367.
73. Kaestle, K. L.; Anwer, M. K.; Audhya, T. K.; Goldstein, G. Cleavage of esters using carbonates and bicarbonates of alkali metals: synthesis of Thymopentin. Tetrahedron Lett. 1991, 32, 327-330.
74. The desired product 12 was accompanied by substantial amounts of N-dialkylation product (24%).
75. Abbreviations: EDC, ethyl[3-(dimethylamino)propyl]carbodiimide hydrochloride; HOBt, hydroxybenzotriazole; BOP, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate.
76. Homofarnesol reference: (a) Tamao, K.; Ishida, N.; Kumada, M. (Diisopropoxymethylsilyl)methyl Grignard reagent: A new, practically useful nucleophilic hydroxymethylating agent. J. Org. Chem. 1983, 48, 2120-2122. (b) Tamao, K.; Ishida, N.; Ito, Y.; Kumada, M. Nucleophilic hydroxymethylation of carbonyl compounds: 1-(hydroxymethyl)cyclohexanol. Org. Synth. 1990, 69, 96-105.
77. Homofarnesol reference: (a) Tamao, K.; Ishida, N.; Kumada, M. (Diisopropoxymethylsilyl)methyl Grignard reagent: A new, practically useful nucleophilic hydroxymethylating agent. J. Org. Chem. 1983, 48, 2120-2122. (b) Tamao, K.; Ishida, N.; Ito, Y.; Kumada, M. Nucleophilic hydroxymethylation of carbonyl compounds: 1-(hydroxymethyl)cyclohexanol. Org. Synth. 1990, 69, 96-105.
78. English, A. R.; Girard, D.; Jasys, V. J.; Martingano, R. J.; Kellogg, M. S. Orally effective acid prodrugs of the β-lactamase inhibitor Sulbactam. J. Med. Chem. 1990, 33, 344-347.
79. Farnsworth, C. L.; Marshall, M. S.; Gibbs, J. B.; Stacey, D. W.; Feig, L. A. Preferential inhibition of the oncogenic form of Ras by mutations in the GAP binding/"effector" domain. Cell 1991, 64, 625-633.