Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-04-29
2002-07-02
Naff, David M. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C424S405000, C435S029000, C435S325000, C514S185000, C514S359000
Reexamination Certificate
active
06413952
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to metal complexed receptor ligands, methods for making and identifying them and their use as agonist of dimeric receptors. More specifically, the invention describes a method to promote the oligomerization of dimeric receptors.
BACKGROUND OF THE INVENTION
Many soluble proteins, such as cytokines, hormones and growth factors, exert their functions by binding and activating cell-surface receptors (Arai, K.-I. et al. Annu. Rev. Biochem. 1990, 59, 783; Bazan, J. F. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 6934; Ullrich A. and Schiessinger, J. Cell, 1990, 61, 203-212). These receptors are comprised of three distinct domains: an extracellular ligand-binding domain, a transmembrane domain and a cytoplasmic domain, which is responsible for signal transduction within the cell. Some receptors, such as those for erythropoietin (EPO), thrombopoietin (TPO), and granulocyte-colony stimulating factor (G-CSF), contain the ligand-binding and signal-transduction domains within the same polypeptide subunit. Others, such as receptors for interleukin-2 (IL-2), IL-3 and IL-6 have separate components for ligand-binding and signal transduction. Although the mechanism of receptor activation varies for specific receptor-ligand pairs, a common feature of many single-transmembrane receptors appears to be their aggregation on the cell membrane in response to binding of their specific ligands. This aggregation event can be in the form of homodimerization, in the case of receptors with a single subunit, or heterodimerization, in the case of receptors with different subunits. It has become clear that receptor aggregation is part of the biological signal by which the target cell responds to the presence of specific hormones and growth factors (Young, P. R. “Protein hormones and their receptors”, Curr. Opin. Biotech. 1992, 3, 408-421; Heldin, C. H., “Dimerization of cell surface receptors in signal transduction). Typical examples of such receptors are growth factor receptors with tyrosine kinase activity as well as cytokine receptors.
Monoclonal antibodies have been discovered which have agonist activity to the dimeric receptors such as those from epidermal growth factor (EGF, Fernandez-Pol, J. J. Biol. Chem. 1985, 260, 5003-11; Serrero, G. U.S. Pat. No. 5,723,115), G-CSF (Takahashi, T. et al. J. Biol. Chem. 1996, 271, 17555-17560), tumor necrosis factor (TNF, Fine, S. M. et al. J. Biol. Chem. 1996, 27126, 15303-15306.), growth hormone receptor (Rowlinson, S. W. et al. J. Biol. Chem. 1998, 2739, 5307-5314, EPO (Young, P. R. and Erickson-Miller, C. L. WO 9640231; Chaovapong, W. L. et al. WO 9748729.) and gp130, the common chain for members of the IL-6 family (Fourcin, M. et al. J. Biol. Chem. 1996, 271, 11756-11760). Ability of the monoclonal antibodies to activate the receptors is believed to be due to the presence of the two antigen binding sites, which can bridge the two receptor subunits and facilitate aggregation.
More recently peptides with agonist activity were identified by screening of phage display libraries against the EPO (Wrighton, N. C. et al. Science 1996, 273, 458-463; Wrighton, N. C. et al. U.S. Pat. No. 5,773,569) and TPO receptors (Cwirla, S. E. et al. Science 1997, 276, 1696-1699; Dower, W. J. et al. WO 9640750). The peptides ranged from 14 to 20 residues and activated the receptors by promoting their dimerization on the cell surface. These agonist peptides are unrelated to EPO and TPO and appear to act as dimeric agents, as demonstrated in the crystal structure of the EMPI/EBP complex (Livnah, O. et al. Science 1996, 273, 464-471).
Despite the success of monoclonal antibodies and dimeric peptides in eliciting agonist response in certain dimeric receptors, they are not generally considered desirable candidates for development of pharmaceutical compositions. Lack of oral bioavailability and a limited serum half-life limit the desirability and efficacy of monoclonal antibodies and polypeptides as pharmaceutical agents. Consequently, a need exists for non-antibody ligands which have agonist properties towards dimeric cell-surface receptors.
Notwithstanding the fact that these receptors have been the subject of such research efforts for over a decade, only one application (PCT/US97/08864) describes small organic molecules which exhibit agonist activity towards dimeric cell-surface receptors. This application does not mention metal chelated small organic molecules.
As disclosed herein it has unexpectedly been discovered that metalchelated receptor ligands have agonist properties towards dimeric cell-surface receptors.
SUMMARY OF THE INVENTION
Accordingly, one aspect of the present invention is a method for agonizing dimeric cell-surface receptors which comprises contacting the receptor with a metal chelated receptor ligand including, but not limited to, a zinc chelated receptor ligand.
Another aspect of the invention is a method for identifying agonists of dimeric cell-surface receptors.
A third aspect of the invention relates to metal chelated dimeric cell-surface receptor ligands including, but not limited to, zinc chelated dimeric cell-surface receptor ligands.
A fourth aspect of the invention relates to an isolated receptor binding moiety of a metal chelated dimeric cell-surface receptor ligand including, but not limited to, an isolated receptor binding moiety of a zinc chelated dimeric cell-surface receptor ligand.
A fifth aspect of the invention is a method for making metal chelated dimeric cell-surface receptor ligands including, but not limited to, zinc chelated dimeric cell-surface receptor ligands.
REFERENCES:
patent: 5693515 (1997-12-01), Clark et al.
patent: 5767078 (1998-06-01), Johnson et al.
patent: 5773569 (1998-06-01), Wrighton et al.
patent: 5830851 (1998-11-01), Wrighton et al.
patent: WO99/11262 (1999-03-01), None
Botros et al., “Immobilized metal ion affinity partitioning of cells in aqueous two-phase systems:erythrocytes as a model”,Biochimica et Biophysica Acta, 1074, pp. 69-73 (1991).
Arai et al., “Bleomycin Model Complex Bearing a Carbamoyl Derived Substituent Capable of Coordination to the Chelated Metal Ion As A Sixth Ligand”,Bioorganic&Medicinal Chemistry Letters, 7(1), pp. 15-18 (1997).
Rao et al., Technetium(V) and Rhenium(V) Complexes of 2,3-Bis(mercaptoacetamido)propanoate. Chelate Ring Stereochemistry and Influence on Chemical and Biological Properties,J. Am. Chem. Soc., 112, pp. 5798-5804 (1990).
Katz et al., “Design of potent selective zinc-mediated serine protease inhibitors”,Letters to Nature, 391, pp. 608-613 (1998).
Bergeron et al., “Synthesis and Biological Evaluation of Naphthyldesferrithiocin Iron Chelators”,I. Med. Chem., 39, pp. 1575-1581 (1996).
Chi et al., “Homodimeric and Heterodimeric Bis(amino thiol) Oxometal Complexes with Rhenium(V) and Technetium(V). Control of Heterodimeric Complex Formation and an Approach to Metal Complexes that Mimic Steriod Hormones”,J. Med. Chem., 37, pp. 928-937 (1994).
Wrighton et al., “Small Peptides as Potent Mimetrics of the Protein Hormone Erythropoietin”,Science, 273, pp. 458-463 (1996).
Cwirla et al., “Peptide Agonist of the Thrombopoietin Receptor as Potent as the Natural Cytokine”,Science, 276, pp. 1696-1699 (1997).
Linvah et al., “Functional Mimicry of a Protein Hormone by a Peptide Agonist:The EPO Receptor Complex at 2.8A”,Science, 273, pp. 464-471 (1996).
Klekota et al., “Generation of Novel DNA-Binding Compounds by Selection and Amplification from Self-Assembled Combinatorial Libraries”,Tetrahedron Letters, 38(50), pp. 8639-8642 (1997).
Chi et al., “Selective Formation of Heterodimeric Bis-Bidentate Aminothiol-Oxometal Complexes of Rhenium(V)”,J. Am. Chem. Soc., 115, pp. 7045-7046 (1993).
Routier et al., “Salen-Anthraquinone Conjugates. Synthesis, DNA-Binding and Cleaving Properties, Effects on Topoisomerases and Ctotoxicity”,Bioorganic&Medicinal Chemistry, 4(8), pp. 1185-1196 (1996).
Gleason John G.
Luengo Juan I.
Miller Stephen G.
Dustman Wayne J.
Kinzig Charles M.
Naff David M.
SmithKline Beecham Corporation
Venetianer Stephen
LandOfFree
Agonizing dimeric cell-surface receptors with a receptor... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Agonizing dimeric cell-surface receptors with a receptor..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Agonizing dimeric cell-surface receptors with a receptor... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2832285