Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-12
2004-05-25
Kim, Vickie (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S464000, C514S466000
Reexamination Certificate
active
06740665
ABSTRACT:
FIELD OF THE INVENTION
The present invention is related to tyrosine kinase inhibitors, pharmaceutical compositions that comprise the same, and methods of using tyrosine kinase inhibitors to inhibit elevated tyrosine kinase activity associated with tumors that express p185. The present invention relates to methods of treating individuals who have cancer characterized by tumors with cells that express p185.
BACKGROUND OF THE INVENTION
The erbB family of receptors includes erbB1 (EGFR), erbB2 (p185), erbB3 and erbG4. Ullrich, et al. (1984)
Nature
309,418-425, which is incorporated herein by reference, describes EGFR. Schechter, A. L., et al. (1984)
Nature
312, 513-516, and Yamamoto, T., et al.(1986)
Nature
319, 230-234, which are each incorporated herein by reference, describe p185neu/erbB2. Kraus, M. H., et al. (1989)
Proc. Natl. Acad. Sci. USA
86, 9193-9197 which is incorporated herein by reference, describes erbB3 Plowman, G. D., (1993)
Proc. Natl. Acad. Sci. USA
90, 1746-1750, which is incorporated herein by reference, describes erbB4.
The rat cellular protooncogene c-neu and its human counterpart c-erbB2 encode 185 kDa transmembrane glycoproteins termed p185. Tyrosine kinase (tk) activity has been linked to expression of the transforming phenotype of oncogenic p185 (Bargmann et al.,
Proc. Natl. Acad. Sci. USA
, 1988, 85, 5394; and Stem et al.,
Mol. Cell. Biol.,
1988, 8, 3969, each of which is incorporated herein by reference). Oncogenic neu was initially identified in rat neuroglioblastomas (Schechter et al.,
Nature,
1984, 312, 513, which is incorporated herein by reference) and was found to be activated by a carcinogen-induced point mutation generating a single amino acid substitution, a Val to Glu substitution at position 664, in the transmembrane region of the transforming protein (Bargmann et al., Cell, 1986, 45, 649, which is incorporated herein by reference). This alteration results in constitutive activity of its intrinsic kinase and in malignant transformation of cells (Bargmann et al.,
EMBO J.,
1988, 7, 2043, which is incorporated herein by reference). The activation of the oncogenic p185 protein tyrosine kinase appears to be related to a shift in the molecular equilibrium from monomeric to dimeric forms (Weiner et al.,
Nature,
1989, 339, 230, which is incorporated herein by reference).
Overexpression of c-neu or c-erbB2 to levels 100-fold higher than normal (i.e., >10
6
receptors/cell) also results in the transformation of NIH3T3 cells (Chazin et al.,
Oncogene,
1992, 7, 1859; DiFiore et al.,
Science,
1987, 237, 178; and DiMarco et al.,
Mol. Cell. Biol.,
1990, 10, 3247, each of which is incorporated herein by reference). However, NIH3T3 cells or NR6 cells which express cellular p185 at the level of 10
5
receptors/cell are not transformed (Hung et al.,
Proc. Natl. Acad. Sci. USA,
1989, 86, 2545; and Kokai et al.,
Cell,
1989, 58, 287, each of which is incorporated herein by reference), unless co-expressed with epidermal growth factor receptor (EGFR), a homologous tyrosine kinase (Kokai et al.,
Cell,
1989, 58, 287, which is incorporated herein by reference). Thus, cellular p185 and oncogenic p185 may both result in the transformation of cells.
Cellular p185 is highly homologous with EGFR (Schechter et al.,
Nature,
1984, 312, 513; and Yarnamoto et al.,
Nature,
1986, 319, 230, each of which is incorporated herein by reference) but nonetheless is distinct. Numerous studies indicate that EGFR and cellular p185 are able to interact (Stern et al.,
Mol. Cell. Biol.,
1988, 8, 3969; King et al.,
EMBO J,
1988, 7, 1647; Kokai et al.,
Proc. Natl. Acad. Sci. USA,
1988, 85, 5389; and Dougall et al.,
J. Cell. Biochem.,
1993, 53, 61; each of which is incorporated herein by reference). The intermolecular association of EGFR and cellular p185 appear to up-regulate EGFR function (Wada et al.,
Cell,
1990, 61, 1339, which is incorporated herein by reference). In addition, heterodimers which form active kinase complexes both in vivo and in vitro can be detected (Qian et al.,
Proc. Natl Acad Sci. USA.
1992, 89, 1330, which is incorporated herein by reference).
Similarly, p 185 interactions with other erbB family members have been reported (Carraway et al.,
Cell
1994, 78, 5-8; Alroy et al.,
FEBS Lett.
1997, 410, 83-86; Riese et al.,
Mol. Cell. Biol.
1995, 15, 5770-5776;Tzahar et al.,
EMBO J,
1997, 16, 4938-4950; Surden et al.,
Neuron
1997, 18, 847-855; Pirlcas-Kramarski et al.,
Oncogene
1997, 15, 2803-2815; each of which is incorporated herein by reference). Human p185 forms heterodimers with either erbB3 or erbB4 under physiologic conditions, primarily in cardiac muscle and the nervous system, particularly in development.
Cellular p185 proteins are found in adult secretory epithelial cells of the lung. salivary gland, breast, pancreas, ovary, gastrointestinal tract, and skin (Kokal et al.,
Proc. Natl. Acad. Sci. USA,
1987, 84, 8498; Mori et al.,
Lab, Invest.,
1989, 61, 93; and Press et al.,
Oncogene,
1990, 5, 953; each of which is incorporated herein by reference). Recent studies have found that the amplification of c-erbB2 occurs with high frequency in a number of human adenocarcinomas such as gastric (Akivama et al.,
Science,
1986, 232, 1644, which is incorporated herein by reference), lung (Kern et al.,
Cancer Res.,
1990, 50, 5184, which is incorporated herein by reference) and pancreatic adenocarcinomas (Williams et al.,
Pathobiol.,
1991, 59, 46, which is incorporated herein by reference). It has also been reported that increased c-erbB2 expression in a subset of breast and ovarian carcinomas is linked to a less optimistic clinical prognosis (Slamon et al.,
Science,
1987, 235, 177; and Slamon et al.,
Science,
1989, 244, 707, each of which is incorporated herein by reference). Heterodimeric association of EGFR and p185 has also been detected in human breast cancer cell lines, such as SK-Br-3 (Goldman et al.,
Biochemistry,
1990, 29, 11024, which is incorporated herein by reference), and transfected cells (Spivak-Kroizman et al.,
J. Biol. Chem.,
1992, 267, 8056, which is incorporated herein by reference). Additionally, cases of erbB2 and EGFR coexpression in cancers of the breast and prostate have been reported. In addition, heterodimeric association of p185 and erbB3 as well as heterodimeric association of p185 and erbB4 have also been detected in human cancers. Coexpression of erbB2 and erbB3 has been observed in human breast cancers. Coexpression of EGFR, erbB2, and erbB3 has been seen in prostate carcinoma.
As used herein, the term “p185” is meant to refer to the neu gene product and the erbB-2 gene product which are 185 kdalton receptor proteins as determined by carrying out electrophoresis on the glycoprotein and comparing its movement with marker proteins of known molecular weight. p185 has tyrosine kinases activity, forms homodimers with themselves and interacts with other members of the erbB family, such as erbB1 (epidermal growth factor receptor or EGFR), erbB3 and erbB4 to form heterodimers.
As used herein, the term “p185 tumors”, “neu-associated cancer”, “neu-associated tumors” and “p185-associated tumors” are used interchangably and are meant to refer to tumors with cells that express p185. A p185 tumor may contain cells that express p185 and, additionally, other members of the erbB family, such as erbB1 (EGFR), erbB3 and erbB4 to form heterodimers and EGFR. A p185 tumor may contain p185 homodimers and/or heterodimers including p185-EGFR heterodimers and/or p185-erbB3 heterodimers and/or p185-erbB4 heterodimers. Dimerization of p185 with other p185 molecules or other members of the p185 family is associated with elevated tyrosine kinase activity. Examples of p185 tumors include many human adenocarcinomas such as some breast, ovary, lung, pancreas, salivary gland, kidney, prostate adenocarcinomas and some neuroblastoma.
As used herein, the term “p185-mediated cellular transformation” is meant to refer to the cellular transformation that p185-associated tumor cell neoplasms undergo and whose tran
Greene Mark I.
Murali Ramachandran
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