Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-03
2003-03-18
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S338000, C514S339000, C546S275700, C548S359100
Reexamination Certificate
active
06534655
ABSTRACT:
BACKGROUND OF THE INVENTION
Protein tyrosine kinases (PTKs) comprise a large and diverse class of proteins having enzymatic activity. The PTKs play an important role in the control of cell growth and differentiation (for review, see Schlessinger & Ullrich, 1992
, Neuron
9:383-391).
For example, receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signalling molecules that facilitate the appropriate cellular response. (e.g., cell division, metabolic effects, responses to the extracellular microenvironment) see Schlessinger and Ullrich, 1992
, Neuron
9:1-20.
With respect to receptor tyrosine kinases, it has been shown also that tyrosine phosphorylation sites function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules (Fantl et al., 1992
, Cell
69:413-423; Songyang et al., 1994
, Mol. Cell. Biol
. 14:2777-2785; Songyang et al., 1993
, Cell
72:767-778; and Koch et al., 1991
, Science
252:668-678). Several intracellular substrate proteins that associate with receptor tyrosine kinases (RTKs) have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such a domain but serve as adapters and associate with catalytically active molecules (Songyang et al., 1993
, Cell
72:767-778). The specificity of the interactions between receptors or proteins and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors are consistent with the observed differences in their substrate phosphorylation profiles (Songyang et al., 1993
, Cell
72:767-778). These observations suggest that the function of each receptor tyrosine kinase is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signalling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors.
Aberrant stimulation, expression or mutations in the PTKs have been shown to lead to either uncontrolled cell proliferation (e.g., malignant tumor growth) or to defects in key developmental or reparative processes. Consequently, the biomedical community has expended significant resources to discover the specific biological role of members of the PTK family, their function in differentiation processes, their involvement in tumorigenesis and in other diseases, the biochemical mechanisms underlying their signal transduction pathways activated upon ligand stimulation and the development of novel drugs.
Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
Receptor Tyrosine Kinases (RTKs). The RTKs comprise a large family of transmembrane receptors with diverse biological activities. The receptor tyrosine kinase (RTK) family includes receptors that are crucial for the growth and differentiation of a variety of cell types (Yarden and Ullrich,
Ann. Rev. Biochem
. 57:433-478, 1988; Ullrich and Schlessinger,
Cell
61:243-254, 1990). The intrinsic function of RTKs is activated upon ligand binding, which results in phosphorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses (Ullrich & Schlessinger, 1990
, Cell
61:203-212).
At present, at least nineteen (19) distinct RTK subfamilies have been identified. One RTK subfamily, designated the HER subfamily, is believed to be comprised of EGFR, HER2, HER3, and HER4. Ligands to the HER subfamily of receptors include epithelial growth factor (EGF), TGF-&agr;, amphiregulin, HB-EGF, betacellulin and heregulin. Aberrant regulation of HER2/erbB2 kinase activity is believed to promote a transformed tumorigenic phenotype especially in breast carcinomas. Two other RTK subfamilies are designated the insulin receptor subfamily, which is comprised of INS-R, IGF-1R and IR-R, and “PDGFR” subfamily which includes the PDGF&agr; and &bgr;-receptors, CSF-1R, and c-kit.
Several receptor tyrosine kinases, and growth factors that bind thereto, have been suggested to play a role in angiogenesis, although some may promote angiogenesis indirectly (Mustonen and Alitalo,
J. Cell Biol
. 129:895-898, 1995). One such receptor tyrosine kinase, known as fetal liver kinase 1 (flk-1), is a member of the type III subclass of RTKs. An alternative designation for human flk-1 is kinase insert domain-containing receptor (KDR) (Terman et al.,
Oncogene
6:1677-83, 1991). Another alternative designation for flk-1/KDR is “vascular endothelial cell growth factor receptor 2” (VEGFR-2). The murine version of flk-1/VEGFR-2 has also been called NYK (Oelrichs et al,
Oncogene
8 (1):11-15, 1993). DNAs encoding mouse, rat and human flk-1 have been isolated, and the nucleotide and encoded amino acid sequences reported (Matthews et al.,
Proc. Natl. Acad. Sci. USA
, 88:9026-30, 1991; Terman et al., 1991, supra; Terman et al.,
Biochem. Biophys. Res. Comm
. 187:1579-86, 1992; Sarzani et al., supra; and Millauer et al.,
Cell
72:835-846, 1993).
The type III subclass RTK designated fms-like tyrosine kinase-1 (flt-1) is related to flk-1/KDR (DeVries et al.
Science
255;989-991, 1992; Shibuya et al.,
Oncogene
5:519-524, 1990). An alternative designation for flt-1 is “vascular endothelial cell growth factor receptor 1” (VEGFR-1). To date, members of the flk-1/KDR/VEGFR-2 and flt-1/VEGFR-1 subfamilies have been found expressed primarily on endothelial cells. These subclass members are specifically stimulated by members of the vascular endothelial cell growth factor (VEGF) family of ligands (Klagsburn and D'Amore,
Cytokine & Growth Factor Reviews
7: 259-270, 1996). Flt-1 is believed to be essential for endothelial organization during vascular development. Flt-1 expression is associated with early vascular development in mouse embryos, and with neovascularization during wound healing (Mustonen and Alitalo, supra). Expression of flt-1 in adult. organs suggests an additional function for this receptor that is not related to cell growth (Mustonen and Alitalo, supra).
Another RTK that is related to flt-1 and flk-1/KDR is flt-4 (Galland et al.,
Oncogene
8:1233-40, 1993; Pajusola et al.,
Oncogene
8:2931-37, 1993). Features shared by these three receptors include the seven immunoglobulin-like domains in their extracellular region. The amino acid sequence of flt-4 exhibits significant homology with the sequences of flt-1 and flk-1, especially in the tyrosine kinase domain (Galland et al., supra). Unlike flt-1 and flk-1/KDR, however, a precursor form of flt-4 is cleaved during post-translational processing to form two disulfide-linked polypeptides (Pajusola et al., supra). Studies of flt-4 expression during development support the theory of venous origin of lymphatic vessels (Kaipainen et al.,
Proc. Natl. Acad. Sci. USA
92:3566-70, April, 1995).
Given the crucial role of endothelial cells in angiogenesis, growth factors that act on endothelial cells are of particular interest for studies of the regulation of vascularization. One such factor is vascular endothelial cell growth factor (VEGF), which binds to both Flk-1 and Flt-1 with relatively high affinity and is mitogenic toward vascular endothelial cells (Terman et al., 1992, supra; Mustonen et al. supra; DeVries et al., supra). VEGF does not bind to flt-4 (Pajusola et al., su
Arnold Lee D.
Barlozzari Teresa
Hockley Michael
Rafferty Paul
Turner Allyson
Coppins Janet
O'Brien Gayle B.
Rotman Alan L.
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