Description of Invention:
The present invention relates to novel phenylalanine derivatives, compositions and methods of using said derivatives to inhibit SH2 domain binding with a phosphoprotein. Additionally, the invention provides precursors suitable for preparing these phenylalanine derivatives.
The therapy and prophylaxis of proliferative diseases such as cancer, autoimmune disorders and hyperproliferative skin disorders can involve signal transduction. These signal-pathways are critical to normal cellular homeostasis and are necessary processes for relaying extracellular messages from various sources, e.g., growth factors, hormones or neurotransmitters, via receptors to the interior of the cell. Protein-tyrosine kinases are integral participants of many of these pathways, and they are responsible for the phosphorylation of specific tyrosine residues to form tyrosine phosphorylated residues. These pathways can involve complex networks which contain proteins with specific amino acid sequences called "Src-homology 2" (SH2) domains. Malfunctions in these protein-tyrosine phosphorylations through tyrosine kinase overexpression or deregulation, can manifest a variety of oncogenic and proliferative disorders. SH2 domain containing proteins that play roles in cellular signaling and transformation include, but are not limited to: Src, Lck, Ras GTPase-activating protein, Phospholipase C, PI-3 kinase, Grb2, BCR Abl and Tyk2. Central to the binding of SH2 domains with phosphotyrosine (pTyr)-containing ligands is the interaction of a doubly ionized pTyr phosphate with two highly conserved arginine residues. These interactions are critical, and binding is usually lost by removal of the phosphate group. While the pTyr-pharmacophore therefore plays a dominant role in SH2 domain-ligand interactions, pTyr residues are not suitable components of inhibitors intended for in vivo application, due to the enzymatic lability of the phosphate ester bond and the poor cellular penetration of the doubly ionized phosphate species. Therefore, a need exists for non phosphate containing compounds that can mimic the structural interactions of phosphotyrosyl residues within SH2 domain pTyr-binding sites, and in so doing disrupt the interactions between SH2 domains of proteins, e.g., Grb2, and proteins with phosphorylated moieties. The disclosed invention provides viable candidates for these compounds and could provide for the development of therapeutic agents for the treatment of proliferative diseases or conditions as well as relevant diagnostic or testing procedures.
