Development of SHP-2 Phophatase Inhibitors

Swarthmore College, Swarthmore PA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): In recent years, structural analysis of signaling proteins has led to important advances in understanding the regulation of cellular signal transduction pathways. However, it still remains a challenge to be able to combine protein structural and functional information to design small molecule ligands that can be used to study the biological roles of proteins. The overall goal of this research project is to develop small cyclic non-phosphorylated peptides that specifically inhibit protein tyrosine phosphatase, SHP-2, in order to probe the role of this enzyme in cellular signaling. SHP-2 is a widely expressed cytoplasmic tyrosine phosphatase involved in growth factor, cytokine, hormone, and immune signaling. In several studies, SHP-2 has been found to be a positive mediator of growth factor signal transduction, acting upstream of mitogen activated protein (MAP) kinase pathways, and effecting cellular developmental processes. It has recently been found that the genetic cause of the developmental disorder Noonan syndrome, characterized by dysmorphic facial features, short stature, heart disease, and skeletal malformations can be mapped to mutations in SHP-2. It is hypothesized that these mutations lead to increased SHP-2 phosphatase activity that would effect growth factor receptor signaling. The link between SHP-2 activity and the activation of cell growth also suggests that SHP-2 may be involved in tumorigenesis and therefore, a potential target for anti-cancer drugs. Cyclic peptide inhibitors of SHP-2 will be designed based on the existing crystal structure of the enzyme, which suggests an autoinhibitory mechanism by the N-terminal src-homology 2 (SH2) domain of the protein. Different synthetic cyclization strategies will be applied and combined with structural information obtained from proton nuclear magnetic resonance (1H-NMR) studies to develop constrained peptides with high inhibitory activity. Inhibitors with the highest potency and selectivity will then be delivered into cells and tested for their effect on the epidermal growth factor (EGF) receptor signaling pathway by determining the phosphorylation state of different proteins in the MAP kinase pathway upon stimulation of the cells with EGF. These studies will give new insights into the molecular details of SHP-2's mode of action, including its substrate(s), and the effects of its inhibition in cellular responses to growth factors. Understanding the regulation of SHP-2 can establish this protein as a target for the development of therapeutic drugs for cellular disorders. [unreadable] [unreadable]