Protein tyrosine phosphatase-inhibiting compounds

Details Protein tyrosine phosphatase-inhibiting compounds Protein tyrosine phosphatase-inhibiting compounds

2000-08-24

2002-05-14

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C514S234200, C514S234500

Reexamination Certificate

active

06388076

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel protein tyrosine phosphatase modulating compounds, to methods for their preparation, to compositions comprising the compounds, to their use for treatment of human and animal disorders, to their use for purification of proteins or glycoproteins, and to their use in diagnosis. The invention relates to modulation of the activity of molecules with phosphotyrosine recognition units, including protein tyrosine phosphatases (PTPases) and proteins with Src-homology-2 domains, in in vitro systems, microorganisms, eukaryoic cells, whole animals and human beings.
BACKGROUND OF THE INVENTION
Reversible phosphorylation of proteins is a prevalent biological mechanism for modulation of enzymatic activity in living organisms. Tonks et al.,
J. Biol. Chem
., 263(14):6722-30 (1988). Such reversible phosphorylation requires both a protein kinase (PK), to phosphorylate a protein at a particular amino acid residue, and a protein phosphatase (PP), to remove the phosphate moieties. See generally, Hunter,
Cell
, 80:225-236 (1995). Recently, it has been estimated that humans have as many as 2000 conventional PK genes, and as many as 1000 PP genes. Id.
One major class of PK's/PP's—the protein seine/threonine kinases and protein serine/threonine phosphatases—have been shown to play critical roles in the regulation of metabolism. See generally, Cohen,
Trends Biochem. Sci
., 17:408-413 (1992); Shenolikar,
Ann. Rev. Cell Biol
., 10:55-86 (1994); Bollen et al.,
Crit. Rev. Biochem. Mol. Biol
., 27:227-81 (1992). As their name suggests, these enzymes phosphorylate and dephoshphorylale serine or threonine residues of substrate proteins. Inhibitors of prntein serine/threonine phosphatases and kinases have been described. See, e.g., MacKintosh and MacKintosh,
TIBS
, 19:444-448 (1994).
The protein tyrosine kinases/phosphatases comprise a second, distinct family of PK/PP enzymes of significant interest, and have been implicated in the control of normal and neoplastic cell growth and proliferation. See Fisher et al.,
Science
, 253:401-406 (1991) Protein tyrosine kinase (PTK) genes are ancient in evolutionary origin and share a high degree of inter-species conservation. See generally Hunter and Cooper,
Ann. Rev. Biochem
., 54:897-930 (1985). PTK enzymes exhibit high specificity for tyrosine, and ordinarily do not phosphorylate serine, threonine, or hydroxyproline.
More than 75 members of the PTPase family have been identified in eukaryotes, prokaryotes, and even viruses. Tonks and Neel,
Cell
87:365-368. Protein tyrosine phosphatases (PTPases) were originally identified and purified from cell and tissue lysates using a variety of artificial substrates, and therefore their natural functions and substrates were not obvious. However, their roles in cellular processes including cell-cell contact and cell adhesion, and growth factor and antigen signaling events, have begun to be elucidated.
PTPases are generally grouped into two categories: those which have both an extracellular domain and an intracellular catalytic domain, the receptor PTPases (R-PTPases); and those which are entirely intracellular. For R-PTPases much effort has been directed at determining the function of the extracellular domain. Most of the R-PTPases contain extracellular domains which are structurally similar to domains found in known adhesion molecules; these domains include fibronectin type III repeats, immunoglobulin domains, and cadherin extracellular repeats. See generally Brady-Kalnay and Tonks,
Curr. Opin. Cell. Biol
. 7:650-657 (1995); Streuli,
Curr. Opin. Cell. Biol
. 8:182-188 (1996). This homology with proteins known to be involved in adhesion suggested a role for these R-PTPase in regulating or mediating adhesion events. For several of the R-PTPases, this has now been demonstrated.
Cells form specialized structures at the sites of cell-cell contact (adherens junctions) and cell-extracellular matrix contact (focal adhesion). Multiple signal transduction molecules are recruited to these sites, including several PTK's; and these sites are characterized by increased protein tyrosine phosphorylation. These sites are impermanent, and are created and destroyed as required for cell mobility. As enhanced tyrosine phosphorylation is characteristic of the formation of adherens junctions and focal adhesions, it is likely that protein tyrosine dephosphorylation by PTPases serves to regulate the creation and destruction of the sites. Supporting this, several studies have shown that treatment with a general PTPase inhibitor (vanadate) resulted in increased focal adhesion formation and increased cell spreading. Volberg et al.,
The EMBO J
. 11:1733-1742 (1992); Bennett al,.
J. Cell Sci
. 106:891-901 (1993). Importantly, the broadly-expressed LAR R-PTPase has been demonstrated to localize to focal adhesions, apparently via the LAR-interacting protein LIP.1. Serra-Pages et al.,
The EMBO J
. 14:2827-2838 (1995). As PTP&dgr; and PTP&sgr;, both R-PTPases, also associate with LIP.1 [Pulido et al.,
Proc. Natl. Acad. Sci
. 92:11686-11690 (1995)], it is likely that these two phosphatases can also localize to focal adhesions. Most significantly, LAR only localized to the portion of the focal adhesion which is proximal to the nucleus, and is thought to be undergoing disassembly. Thus it is likely that these phosphatases act to negatively regulate focal adhesion formation, acting to enhance the destruction of the focal adhesion site.
R-PTPases may also act to positively regulate adhesion. Adherens junctions contain, among others, adhesion receptors termed cadherins which mediate cell-cell contact through homophilic binding; the cadherins associate with &agr;-, &bgr;-, and &ggr;-catenins, intracellular proteins which interact with cortical actin. Association between cadherins and catenins serves to stabilize the adherens junction and to strengthen cell-cell contact. See generally Cowin,
Proc. Natl. Acad. Sci
. 91:10759-10761 (1994). Association of cadherin with &bgr;-catenin is decreased by tyrosine phosphorylation of &bgr;-catenin [Kinch el al.,
J. Cell. Biol
. 130:461-471 (1995); Behrens et al.,
J. Cell. Biol
. 120:757-766 (1993)]; moreover, treatment with the PTPase inhibitor vanadate inhibits cadherin-dependent adhesion [Matsuyoshi et al.,
J. Cell. Biol
. 118:703-714 (1992)]. Collectively, these data indicate that PTPase activity is critical in maintaining cadherin-mediated cell aggregation. The R-PTPases PTP&mgr; and PTP&kgr; associate intracellularly with cadherins, and colocalize with cadherins and catenins to adherens junctions [Brady-Kalnay et al.,
J. Cell. Biol
. 130:977-986 (1995); Fuchs et al.,
J. Biol. Chem
. 271:16712-16719 (1996)], thus PTP&mgr; and PIT&kgr; are likely to enhance cadherin function by limiting catenin phosphorylation.
In addition to their catalytic function in regulating adhesion events, several R-PTPases have direct roles in mediating adhesion through their extracellular domains. PTP&kgr; and PTP&mgr; mediate cellular aggregation through homophilic binding [Brady-Kalnay et al.,
J. Cell. Biol
. 122:961-972 (1993); Gebbink et al.,
J. Biol. Chem
. 268:16101-16104 (1993); Sap et al,.
Mol. Cell. Biol
. 14:1-9 (1994)]. The neuronal PTP&zgr; (which has also been called R-PTP&bgr;) binds to contactin, a neuronal cell recognition molecule; binding of PTP&zgr; to contactin increases cell adhesion and neuritc outgrowth. Peles et al.,
Cell
82:251-260 (1995). A secreted splice variant of PTP&zgr; (also known as phosphacan) binds the extracellular matrix protein tenascin [Barnea et al.
J. Biol. Chem
. 269:14349-14352 (1994)], and the neural cell adhesion molecules N-CAM and Ng-CAM [Maurel et al.,
Proc. Natl. Acad. Sci
. 91:2512-2516 (1994)]. As the expression of PTP&zgr; is restricted to radial glial cells in the developing central nervous system, which are though to form barriers to neuronal migration during embryogenesis, it is likely that the interaction of PTP&zgr; with con

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