The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is a transducer of growth factor, cytokine, integrin, and hormone signaling pathways that regulate processes such as cell proliferation, differentiation, adhesion, migration, and apoptosis and plays a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2 mutations are associated with several types of leukemias, and solid tumors. This makes SHP2 an attractive target for developing new anticancer therapy. Several small molecules have been developed for inhibition of this important phosphatase, which serve as chemical tools to probe the role of SHP2 in disease and lead compounds for optimization. Nevertheless improvements are required to improve these lead compounds with better potency, selectivity and cell permeability. To gain structural insights for development of potent and selective Shp2 inhibitors, we synthesized a non-hydrolysable phosphotyrosine peptide mimetic, based on reported Shp2 substrate peptide sequences. The non-hydrolyzable phosphopeptide, containing the phosphotyrosyl surrogate difluoromethylphosphonate, was prepared by solid phase peptide synthesis methods from the known building block N-FMOCF2Pmp. We will present the synthesis of the peptide, analysis of Shp2 phosphatase inhibition, and binding of the phosphopeptide mimic to SHP2 by micro isothermal calorimetry. We will present a model for the binding mode of the peptide and its implications for the design of selective Shp2 inhibitors.

Citation Format: Harshani R. Lawrence, Yiyu Ge, Andreas Becker, Yuan Ren, Yunting Luo, Jie Wu and Nicholas J. Lawrence. Development of a non-hydrolysable phosphotyrosine mimetic peptide based on a high affinity SHP2 substrate. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2518. doi:10.1158/1538-7445.AM2014-2518