De novo design of nonpeptidic compounds targeting the interactions between interferon-α and its cognate cell surface receptor

Journal of Medicinal Chemistry

Volumn 51, Issue 9, 2008, Pages 2734-2743

  Bello, Angelica M ^a   Bende, Tanushree ^a   Wei, Lianhu ^a   Wang, Xiaoyang ^a   Majchrzak Kita, Beata ^a   Fish, Eleanor N ^a,b,c   Kotra, Lakshmi P ^a,c,d,e  

^a UNIVERSITY HEALTH NETWORK   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

^c UNIVERSITY OF TORONTO   (Canada)

^d UNIVERSITY OF NORTH CAROLINA AT GREENSBORO   (United States)

^e #5 356 Toronto Medical Discoveries Tower/MaRS Center   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

1 [2 [4 [2 (DIMETHYLAMINO)ETHOXY] 6 (2 METHOXYETHYLAMINO)PYRIMIDIN 2 YLOXY]ETHYL]GUANIDINE; 1 [3 [4 [2 (DIMETHYLAMINO)ETHOXY] 6 (2 METHOXYETHYLAMINO)PYRIMIDIN 2 YLOXY]PROPYL]GUANIDINE; 1 [3 [4 [2 (DIMETHYLAMINO)ETHOXY] 6 (3 ISOPROPOXYPROPYL)AMINO]PYRIMIDIN 2 YLOXY]PROPYL]GUANIDINE; 1 [4 [6 [2 (DIMETHYLAMINO)ETHOXY] 2 (2 METHOXYETHYLAMINO)PYRIMIDIN 4 YLOXY]BUTYL]GUANIDINE; 1 [4 [6 [2 (DIMETHYLAMINO)ETHOXY] 2 (3 ISOPROPOXYPROPYLAMINO)PYRIMIDIN 4 YLOXY]BUTYL]GUANIDINE; 2 (2 AMINOETHOXY) 6 [2 (DIMETHYLAMINO)ETHOXY] N (2 METHOXYETHYL)PYRIMIDIN 4 AMINE; 2 (3 AMINOPROPOXY) 6 [2 (DIMETHYLAMINO)ETHOXY] 2 (METHOXYETHYL)PYRIMIDIN 4 AMINE; 2 (3 AMINOPROPOXY) 6 [2 (DIMETHYLAMINO)ETHOXY] N (3 ISOPROPOXYPROPYL)PYRIMIDIN 4 AMINE; 2 [4 (2 AMINOETHYL)PHENOXY] 6 [2 (DIMETHYLAMINO)ETHOXY] N (2 METHOXYETHYL)PYRIMIDIN 4 AMINE; 2 [4 (2 AMINOETHYL)PHENOXY] 6 [2 (DIMETHYLAMINO)ETHOXY] N (3 ISOPROPOXYPROPYL)PYRIMIDIN 4 AMINE; 2 [[4 (2 FURYL)PYRIMIDIN 2 YL]THIO] N,N DIMETHYLETHAMINE; 2 [[4 [2 [[2 (DIMETHYLAMINO)ETHYL]THIO] 6 (2 FURYL)PYRIMIDIN 4 YL]PHENYL]THIO] N,N DIMETHYLETHANAMINE; 2 [[4 [4 [[2 (DIMETHYLAMINO)ETHYL]THIO]PHENYL] 6 (2 THIENYL)PYRIMIDIN 2 YL]THIO] N,N DIMETHYLETHANAMINE; 2,2' [(6 ETHOXYPYRIMIDINE 2,4 DIYL)BIS(OXY)]BIS(N,N DIMETHYLETHANAMINE); 2,2' [(6 ISOPROPOXYPYRIMIDINE 2,4 DIYL)BIS(OXY)]BIS(N,N DIMETHYLETHANAMINE); 2,6 DIISOPROPOXY N (2 METHOXYETHYL)PYRIMIDIN 4 AMINE; 4 (2 AMINOETHOXY) 6 [2 (DIMETHYLAMINO)ETHOXY] N (3 ISOPROPOXYPROPYL)PYRIMIDIN 2 AMINE; 4 (3 AMINOPROPOXY) 6 ETHOXY N (3 ISOPROPOXYPROPYL)PYRIMIDIN 2 AMINE; 4 (3 AMINOPROPOXY) 6 ISOPROPOXY N (3 ISOPROPOXYPROPYL)PYRIMIDIN 2 AMINE; 4 (4 AMINOBUTOXY) 6 [2 (DIMETHYLAMINO)ETHOXY] N (2 METHOXYETHYL)PYRIMIDIN 2 AMINE; 4 (4 AMINOBUTOXY) 6 [2 (DIMETHYLAMINO)ETHOXY] N (3 ISOPROPOXYPROPYL)PYRIMIDIN 4 AMINE; 4 (4 AMINOBUTOXY) 6 ETHOXY N (3 ISOPROPOXYPROPYL)PYRIMIDIN 2 AMINE; 4 [2 (DIMETHYLAMINO)ETHOXY] 6 ETHOXY N (3 ISOPROPOXYPROPYL)PYRIMIDIN 2 AMINE; 4 [2 (DIMETHYLAMINO)ETHOXY] 6 ISOPROPOXY N (3 ISOPROPOXYPROPYL)PYRIMIDIN 2 AMINE; 6 ETHOXY N 2 (3 ISOPROPOXYPROPYL) N 4,N 4 DIMETHYLPYRIMIDINE 2,4 DIAMINE; ALPHA INTERFERON; CELL SURFACE RECEPTOR; N,N DIMETHYL 2 [[4 (2 THIENYL)PYRIMIDIN 2 YL]THIO]ETHANAMINE; RECEPTOR BLOCKING AGENT; UNINDEXED DRUG;

ARTICLE; COMPUTER MODEL; CONTROLLED STUDY; DRUG ACTIVITY; DRUG DESIGN; DRUG SCREENING; DRUG SYNTHESIS; DRUG TARGETING; HUMAN; HUMAN CELL; PROTEIN DNA BINDING; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE;

CELL LINE, TUMOR; DNA; DRUG DESIGN; FURANS; GUANIDINES; HUMANS; INTERFERON-ALPHA; MODELS, MOLECULAR; MOLECULAR MIMICRY; PEPTIDES; PHOSPHORYLATION; PYRIMIDINES; RECEPTOR, INTERFERON ALPHA-BETA; STAT1 TRANSCRIPTION FACTOR; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES;

EID: 42949177992     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm701182y     Document Type: Article

References (35)

1. Platanias, L. C. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 2005, 5, 375-386.
2. Guilhot, F.; Chastang, C.; Michallet, M.; Guerci, A.; Harousseau, J. L.; Maloisel, F.; et al. Interferon α-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia: French myeloid leukemia study group. New Engl. J. Med. 1997, 337, 270-271.
3. Ahmed, A.; Keefe, E. B. Overview of interferon therapy for chronic hepatitis C. Clin. Liver Dis. 1999, 3, 757-773.
4. Vedantham, S.; Gamliel, H.; Golomb, H. M. Mechanism of interferon action in hairy cell leukemia: A model of effective cancer biotherapy. Cancer Res. 1992, 52, 1056.
5. Billiau, A.; Kieseier, B. C.; Hartung, H. P. Biologic role of interferon beta in multiple sclerosis. J. Neurol. 2004, 251, 1110-1114.
6. Lee, P. Y.; Reeves, W. H. Type I interferons as a target of treatment in SLE. Endocr. Metab. Immune Disord. Drug Targets 2006, 6, 323-330.
7. Kyogoku, C.; Tsuchiya, N. A compass that points to lupus: Genetic studies on type I interferon pathway. Genes Immunol. 2007, 8, 445-455.
8. Koutouzov, S.; Mathian, A.; Dalloul, A. Type I interferons and systemic lupus erythematosus. Autoimmun. Rev. 2006, 5, 554-562.
9. Cohen, B.; Novick, D.; Barak, S.; Rubinstein, M. Mol. Cell. Biol. 1995, 15, 4208-4214.
10. Mogensen, K. E.; Lewerenz, M.; Reboul, J.; Lutfalla, G.; Uze, G. The type I interferon receptor: Structure, function and evolution of a family business. J. Interferon Cytokine Res. 1999, 19, 1069-1098.
11. Kurnaran, J.; Wei, L.; Kotra, L. P., Fish, E. N. A structural basis for interferon-α-receptor interactions. FASEB J. 2007, 21, 3288-3296.
12. Chill, J. H.; Nivasch, R.; Levy, R.; Albeck, S.; Schreiber, G.; Anglister, J. The human interferon receptor: NMR-based modeling, mapping of the IFN-α2 binding site, and observed ligand-induced tightening. Biochemistry 2002, 41, 3575-3585.
13. Chill, J. H.; Quadt, S. R.; Levy, R.; Schreiber, G.; Anglister, J. The human type I interferon receptor: NMR Structure reveals the molecular basis of ligand binding. Structure 2003, 791, 802.
14. Platanias, L. C.; Fish, E. N. Signaling pathways activated by interferons. Exp. Hematol. 1999, 27, 1583-1592.
15. Kalvakolanu, D. V. Alternate interferon signaling pathways. Pharmacol. Ther. 2003, 100, 1-29.
16. Fish, E. N. Definition of receptor binding domains in interferon-α. J. Interferon Res. 1992, 12, 257-266.
17. Muller, U.; Steinhoff, U.; Ries, L. F. L.; Hemmi, S.; Pavlovic, J.; Zinkernagel, R. M.; Aguet, M. Functional role of type I and II interferons in antiviral defense. Science 1994, 264, 1918-1921.
18. Yohannes, D. Disruption of protein-protein interactions. Annu. Rep. Med. Chem. 2003, 38, 295-304.
19. Cochran, A. G. Antagonists of protein-protein interactions. Chem. Biol. 2000, 7, R85-R94.
20. Boger, D. L.; Deshrnais, J.; Capps, K. Solution-phase combinatorial libraries: Modulating cellular signalling by targeting protein-protein or protein-DNA interactions. Angew. Chem., Int. Ed. 2003, 4138, 4176.
21. Tan, C.; Wei, L.; Ottensmeyer, F. P.; Goldfine, I.; Yip, C. C.; Batey, R. A.; Kotra, L. P. Structure-based de novo design of ligands using a three-dimensional model of the insulin receptor. Bioorg. Med. Chem. Lett. 2004, 14, 1407-1410.
22. Roisman, L. C.; Piehler, J.; Trosset, J.-Y.; Scheraga, H. A.; Schreiber, G. Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 13231-13236.
23. Klaus, W.; Gsell, B.; Labhardt, A. M.; Wipf, B. The three-dimensional high resolution structure of human interferon α-2a determined by heteronuclear NMR spectroscopy in solution. J. Mol. Biol. 1997, 274, 661-675.
24. Waine, G. J.; Thymms, M. J.; Brandt, E. R.; Cheetham, B. F.; Linnane, A. W. Structure-function study of the region encompassing residues 26-40 of human interferon-α4: Identification of residues important for antiviral and antiproliferative activities. J. Interferon Res. 1992, 12, 43-48.
25. Korn, A. P.; Rose, D. R.; Fish, E. N. Three-dimensional model of a human interferon-α consensus sequence. J. Interferon Res. 1994, 14, 1-9.
26. Unity software program from Tripos Inc. (St. Louis, MO) was used to conduct database searches, in conjunction with Sybyl molecular modeling program. Searches were conducted on an Octane2 dual processor computer or a 44-processor Onyx3800 supercomputer.
27. CAS Registry No. for compound 42, 903633-37-4, and for compound 44, 671188-22-0. All the hit compounds were extracted from either NCI Database, LeadQuest Database or Maybridge database, and these were obtained as part of the UNITY software version 4.0, Tripos Inc., St. Louis, MO.
28. Schinazi, R. F.; Strekowski, L. Unfused heteropolycyclic compounds as visucides, especially against human immunodeficiency virus. PCT/WO 8911279, 1989.
29. Masters, J.; Hinek, A. A.; Uddin, S.; Platanias, L. C.; Zeng, W. Q.; McFadden, G.; Fish, E. N. Poxvirus infection rapidly activates tyrosine kinase signal transduction. J. Biol. Chem. 2001, 276, 48371-48375.
30. Ghislain, J. J.; Fish, E. N. Application of genomic DNA affinity chromatography identifies multiple interferon-alpha-regulated Stat2 complexes. J. Biol. Chem. 1996, 271, 12408-12413.
31. Strekowski, L.; Harden, D. B.; Grubb, W. B.; Patterson, S. E.; Czarny, A.; Mokrosz, M. J.; Cegla, M. T.; Wydra, R. L. Synthesis of 2-chloro-4,6- di(heteroaryl)pyrimidines. J. Heterocycl. Chem. 1990, 27, 1393-1400.
32. Strekowski, L.; Wilson, W. D.; Mokrosz, J. L.; Mokrosz, M. J.; Harden, B. D.; Tanious, F. A.; Wydra, R. L.; Crow, S. A. Quantitative structure-activity relationship analysis of cation-substituted polyaromatic compounds as potentiators (amplifiers) of bleomycin-mediated degradation of DNA. J. Med. Chem. 1991, 34, 580-588.
33. Wilson, W. D.; Strekowski, L.; Tanious, F. A.; Watson, R. A.; Mokrosz, J. L.; Strekowska, A.; Webster, G. D.; Neidle, S. Binding of unfused aromatic cations to DNA - The influence of molecular twist on intercalation. J. Am. Chem. Soc. 1988, 110, 8292-8299.
34. Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. 1H-Pyrazole-1- carboxamidine hydrochloride: An attractive reagent for guanylation of amines and its application too peptide synthesis. J. Org. Chem. 1992, 57, 2497-2502.
35. Brierley, M. M.; Fish, E. N. Stats: Multi-faceted regulators of transcription. J. Interferon Cytokine Res. 2005, 25, 733-744.