Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1999-01-22
2001-10-23
Borin, Michael (Department: 1631)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C514S002600, C514S561000, C514S563000, C530S300000, C548S113000, C548S178000, C548S179000, C548S193000, C548S413000, C560S082000, C562S065000
Reexamination Certificate
active
06307090
ABSTRACT:
The present invention relates to pharmaceutically active compounds comprising a N-oxalyl peptide structure, pharmaceutical preparations comprising said compounds, the compounds for the use in the therapeutic (including propylactic) or diagnostic treatment of the animal or especially human body, and the use of said compounds for the therapeutic or diagnostic treatment of the animal or especially human body or for the manufacture of pharmaceutical preparations.
BACKGROUND OF THE INVENTION
The search for new classes of compounds for the therapy and prophylaxis of proliferative diseases, cancer and metabolic deregulation is one of the most important tasks for pharmaceutical research. These diseases affect a large portion of the population, leading to suffering and often being the cause for the death of the individuals stricken therewith.
Signal transduction is the process of relaying extracellular messages, e.g. chemical messages in the form of growth factors, hormones and neurotransmitters, via receptors, e.g. cell-surface receptors, to the interior of the cell. At the heart of this biological communication are the protein-tyrosine kinases. These enzymes, found, for example, as either transmembrane growth factor receptors or as nuclear or cytosolic non-receptor proteins, catalyze the phosphorylation of specific tyrosine residues. This class of enzymes includes, but is not limited to, the PDGF receptor, the FGF receptor, the HGF receptor, members of the EGF receptor family such as the EGF receptor, the HGF receptor, members of the EGF receptor family such as the EGF receptor, erb-B2, erb-B3 and erb-B4, the src kinase family, Fak kinase and the Jak kinase family. The tyrosine-phosphorylated proteins are involved in a range of metabolic processes, from proliferation and growth to differentiation. Protein-tyrosine phosphorylation is known to be involved in modulating the activity of some target enzymes as well as in generating specific complex networks involved in signal transduction via various proteins containing a specific amino acid sequence called a Src Homology region or SH2 domain (for review see Proc. Natl. Acad. Sci. USA 90, 5891 (1990)). A malfunction in this protein-tyrosine phosphorylation through tyrosine kinase overexpression or deregulation is manifested by various oncogenic and (hyper-)proliferative disorders such as cancer, inflammation, autoimmune disease, hyperroliferative skin disorders, such as psoriasis, and allergy/asthma.
SH2- and/or SH3-comprising proteins that play a role in cellular signaling and transformation include, but are not limited to, the following: Src, Lck, Eps, ras GTPase-activating protein (GAP), phospholipase C, phosphoinositol-3 (Pl-3)kinase, Fyn, Lyk, Fgr, Fes, ZAP-70, Sem-5, p85, SHPTP1, SHPTP2, corkscrew, Syk, Lyn, Yes, Hck, Dsrc, Tec, Atk/Bpk, Itk/Tsk, Arg, Csk, tensin, Vav, Emt, Grb2, BCR-Abl, Shc, Nck, Crk, CrkL, Syp, Blk, 113TF, 91TF, Tyk2, esecially Src, phospholipase c, phoshoinositol-3 (pl-3) kinase, Grb2, BCR-Abl, Shc, Nck, Crk and CrkL.
A direct link has been established between activated receptor kinases and Ras with the finding that the mammalian Grb2 protein, a 26 kilodalton protein comprising a single SH2 and two SH3 domains bind to proline-rich sequences present in the Sos exchange factor.
The significance of ras-regulatory proteins in human tumors is also highlighted by the critical role of GRB2 in BCR-Abl mediated oncogenesis (J. Exp. Med., 179(1), 167-175 (1994)).
Recently, DNA sequences within the chromosomal locus 17q22-qter, which harbors the GRB2 gene, were shown by comparative genomic hybridization to exhibit a high frequency of amplification both human breast cancer cell lines and tumors (Proc. Natl. Acad. Sci. USA 91, 2156-2160 (1994)).
In a study of GRB2 gene expression in human breast cancer cell lines, Northern Blot analysis also revealed that 7/19 breast cancer cell lines exhibited more than 2 fold overexpression of GRB2 MRNA relative to normal breast epithelial cells. In MCF-7, MDA-MB-361, and -453 cells, the overexpression of GRB2 MRNA was accompanied by a 10-20 fold increase in the amount of GRB2 protein (Oncogene 9, 2723 (1994)).
SH2 domains represent recognition motifs for specific tyrosine-phosphorylated peptide sequences. Short, conserved motifs, primarily 3 to 6 amino acid on the carboxy-terminal side of phosphotyrosine residue, carry the sequence-specific information for SH2-recognition. This concept has been supported by the mapping of separate sites for binding of SH2 domains from different signaling molecules on various receptors [see, e.g., Cell 69, 413 (1992); Proc. Natl. Acad. Sci. USA 89, 678 (1992); Mol. Cell. Bio. 12, 991 (1992); EMBO J. 11, 1365 (1992); EMBO J. 11, 559 (1992); EMBO J. 11, 3911 (1992): Cell 73, 321 (1993)]. Degenerate peptide libraries have also been used to predict the specifity of individual SH2 domains (src family members, Abl, Nck, Sem5, phospholipase C-&ggr;, p85 subunit of Pl-3 kinase, and HCP (amino terminal SH2) [see Cell 72, 767 (1993); Mol. Cell. Biol. 14, 2777 (1994)]). High-resolution crystallographic analysis and nuclear magnetic resonance of the SH2 domains of Src, Lck, PLC-&ggr; C-terminal, p85 N-terminal, Abl, Syp C-terminal have also revealed that the region on the carboxyl side of the phosphotyrosine carries the sequence-specific information for SH2 recognition. Each of these SH2 containing proteins controls a cellular pathway involved in the biological response to a growth factor. Activation of a particular pathway can thus be inhibited by designing a small molecule that specifically disrupts a phosphoprotein/SH2 domain interaction.
Src homology 2 (SH2) domains are protein motifs which recognize and bind with high affinity to phosphotyrosyl (pTyr, 1)-containing proteins. These modules serve critical roles in protein-tyrosine kinase (PTK) pathways by protein-protein oligomerization in response to specific signalling events.
1
The growth factor receptor-bound 2 (Grb2) SH2 domain is a key link in mitogenic Ras pathways, functioning as a bridging element between cell surface growth factor receptors and the Ras protein. Grb-2 mediated activation of Ras pathway is highly relevant to a number of diseases, including breast cancer, where members of the epidermal growth factor receptor (EGFR) PTK family such as erbB-2 (HER-2
eu) are frequently over-expressed.
2
Progress in the development of novel high affinity Grb2 SH2 domain ligands
3-5
is typified by 11,
6
whose design is based on binding of a larger pTyr-containing peptide to the Grb2 SH2 domain in &bgr;-bend fashion.
7
While these inhibitors take advantage of high affinity interactions with SH2 domains outside the pTyr-binding pocket, finding suitable phosphatase-resistant replacements for the pTyr residue itself has continued to be a challenge.
8
In the area of non phosphorus-containing phosphate alternatives, analogues (9) of 4,5-dideoxyshikimate-3-phosphate (8) first demonstrated the utility of the malonate group as a phosphate mimetic.
9
. Based on this work, the dicarboxylic-containing O-malonyl-L-tyrosine (OMT, 4)
10
was prepared on a non-phosphorus-containing pTyr mimetic. Although OMT residues are moderately potent against a variety of SH2 domains,
11
they share with parent pTyr the disadvantage of two negative charges. Efforts are therefore underway to identify monocarboxylic-based pTyr mimetics for use in Grb2 SH2 domain antagonists.
Signal transduction is critical to normal cellular homeostasis, with abberations in some signalling pathways having potentially adverse effects, including the promotion of cancers and immune disorders. For many growth factor and cytokine pathways, binding of extracellular ligands results in intracellular signalling through the phosphorylation of tyrosyl residues by protein-tyrosine kineses (PTKs). This can result in subsequent signal transduction through protein-protein binding mediated by Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains, which recognize with high affinity, specific pTyr-containing sequences.
12,13
The phosphotyr
Burke, Jr. Terrence R.
King C. Richter
Yao Zhu-jun
Borin Michael
The United States of America as represented by the Department of
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