Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-08-16
2000-11-07
Lambkin, Deborah C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514255, 540575, 544374, 530350, 5303893, A61K 3133, A61K 31495, C07K 100, C07K 1600
Patent
active
061437409
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Members of the EGF receptor family, including the EGFR, erbB-2
eu, erbB-3 and erbB-4 genes are overexpressed in at least 60-70% of human breast cancers. Targeted inhibition of the erbB receptor(s) with monoclonal antibodies, immunotoxins or antisense oligonucleotides has been reported and some have reached early phase clinical trials. Several major therapeutic limitations are associated with these approaches, including large molecule size, poor tissue penetration, delivery, and host immune responses.
Attempts to isolate a ligand for erbB-2
eu led to the discovery of gp30, or heregulin (HRG or NDF) (Lupu et al., Science, 256:1205-1210, 1992; Holmes et al., Science 256:1205-1210, 1992; Peles et al., Cell, 69:205-216, 1992). HRG contains an EGF-like domain which is effective to bind and stimulate of p185.sup.erbB phosphorylation. The EGF-like domain of HRG contains six cysteine residues that are characteristic of the EGF family of growth factors, but HRG does not bind to EGF receptors (Holmes et al., Science 256:1205-1210, 1992; Peles et al., Cell, 69:205-216, 1992; Falls et al., Cell, 72:801-815, 1993; Marchionni et al., Nature, 362:312-318, 1993; Peles et al., Bioessays, 15:815-824, 1993). Both erbB-3 and erbB-4 are receptors for HRG (Plowman et al., Nature, 366:473-475, 1993; Carraway et al., Cell, 78:5-8, 1994; Tzahar et al., J. Biol. Chem. 269:25266-25233, 1994; Carraway et al., J. Biol. Chem. 269:14303-14306, 1994; Kita et al., FEBS Lett., 349:139-143, 1994).
The heregulins (also called neuregulins, NDF, GGF, and ARIA) belong to a family of membrane-bound or secreted proteins produced by neurons and mesenchymal cells. They have multiple effects on a wide range of cell types. Lemke, G. Mol. Cell. Neurosci., vol. 7, 2996, 247-262; and D. Zhang, Proc. Natl. Acad. Sci. USA, vol. 94, 1997, 9562-9567.
It is generally recognized now that the homodimers of erbB-4 are biologically active, whereas the signaling of HRG through erbB-3 is dependent on heterodimerization with other erbB-3 receptors, predominantly the erbB-2 (Carraway et al., Cell, 78:5-8, 1994; Sliwkowski et al., J. Biol Chem. 269:146; Alimandi et al., Oncogene 1995 10(9):1813-21; Chen et al., J. Biol. Chem. 271:7620, 1996).
Expression of HRG has been demonstrated in human breast cancers (Normanno et al., Int. J. Onco. 2:903, 1993; Normanno et al., Breast Cancer Res Treat 1995, 35(3):293-7) and HRG might perform a role in autocrine growth regulation (Carraway et al., Cell, 78:5-8 (1994), progression to estrogen-independent growth and increased tumorigenicity of breast cancer cells (Pietras et al., Oncogene, 1995, 15:10(12):2435-46). Immunostaining studies show that erbB-3 is overexpressed in breast cancer (Lemoine et al., Br. J. Cancer, 66:1116-1121, 1992; Quinn et al., Histopatho., 25:247-252, 1994; Gasparini et al., Eur. J. Cancer, 30A:16-22, 1994), and others (Simpson et al., Br. J. Cancer, 71:758-762, 1995; Myers et al., J. Natl. Cancer Inst. 86:1140-1145, 1994). The expression of erbB-4 is elevated in breast cancer cell lines (Plowman et al., Proc. Natl. Acad. Sci. USA, 90:1746-1750, 1993), and is overexpressed in invasive ductal carcinoma and DCIS of breast but not in the nearby normal breast cells.
Thus, a need exists for specific antagonists of HRG which can function as effective inhibitors of cancer cell growth.
SUMMARY OF THE INVENTION
The present invention provides a therapeutic method to inhibit cancer cell growth comprising administering to a mammal (i.e. a human) in need of such therapy, an amount of a compound of formula (I): ##STR10## wherein R.sub.1 is OH or --CH.sub.2 C(O)N((C.sub.1 -C.sub.4)alkyl).sub.2 ; -C.sub.12)alkyl), --CH.dbd.NOCH(phenyl).sub.2, --CH.dbd.NO(CH.sub.2).sub.n -phenyl, --CH.dbd.N--NHR.sub.9, --CH.dbd.N--R.sub.10 ##STR11## n is 1-6; R.sub.3 and R.sub.4 are each independently H, (C.sub.1 -C.sub.4)alkyl (preferably --CH.sub.3), halo, halo(C.sub.1 -C.sub.4)alkyl, or (C.sub.5 -C.sub.7)aryl optionally comprising 1-2 N, S or non-peroxide O and optionally substituted with (C.sub.1 -C.sub
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Kozikowski Alan P.
Lippman Marc E.
Wang Shaomeng
Yang Dajun
Georgetown University
Lambkin Deborah C.
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