Abstract 3697: Development of a focused non-hydrolyzable phosphopeptide library based on a high affinity SHP2 substrate

Abstract

Abstract The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2), a widely expressed cytoplasmic tyrosine phosphatase with two src-homology 2 (SH2) domains, has received much attention in the signal transduction field. 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 is an attractive target for cancer 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 it is challenging 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-hydrolyzable phosphotyrosine peptide mimetic based on reported SHP2 substrate peptide sequence (10-mer). The non-hydrolyzable phosphopeptide, containing the phosphotyrosyl surrogate difluoromethylphosphonate, was synthesized using solid phase peptide synthesis methods from the known building block N-FMOCF2Pmp and we improved the coupling reaction conditions to generate a peptide library of difluoromethylphosphonate to understand the SHP2 affinity. We will present the synthesis of the peptide library, analysis of SHP2 phosphatase inhibition, and the binding mode (X-ray crystal structure) of the phosphopeptide mimic to SHP2. Citation Format: Harshani R. Lawrence, Yunting Luo, Steven Gunawan, Andreas Becker, Yuan Ren, Ernst Schonbrunn, Jie Wu, Nicholas J. Lawrence. Development of a focused non-hydrolyzable phosphopeptide library based on a high affinity SHP2 substrate. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3697. doi:10.1158/1538-7445.AM2015-3697