Tyrosine phosphatase SHP2 inhibitors in tumor-targeted therapies

Abstract

Src homology containing protein tyrosine phosphatase 2 (SHP2) represents a noteworthy target for various diseases, serving as a well-known oncogenic phosphatase in cancers. As a result of the low cell permeability and poor bioavailability, the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy. Recently, a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified. In particular, few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors. This review summarizes the development and structure-activity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies, with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity, higher oral bioavailability and better physicochemical properties.

Keywords: ALK, anaplastic lymphoma kinase; AML, acute myeloid leukemia; Allosteric inhibitor; B-ALL, B-cell acute lymphoblastic leukemia; BTLA, B and T lymphocyte attenuator; CADD, computer aided drug design; CSF-1, colony stimulating factor-1; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; EGFR, epidermal growth factor receptor; ERK1/2, extracelluar signal-regulated kinase 1/2; FLT3, Fms-like tyrosine kinase-3; GAB2, Grb2-associated binding protein-2; GRB2, growth factor receptor-bound protein 2; HER2, human epidermal growth factor receptor-2; HGF/SF, hepatocyte growth factor/scatter factor; JAK, Janus kinase; KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; MAPK, mitogen-activated protein kinase; NLRP3, NLR family, pyrin domain containing protein 3; PD-1/PDL-1, programmed cell death protein-1/programmed death ligand-1; PDAC, pancreatic ductal adenocarcinoma; PDX, patient-derived xenograft; PI3K, phosphatidylinositol 3 kinase; PTK, protein tyrosine kinase; PTP, protein tyrosine phosphatase; Phosphatase; RAS, rat sarcoma protein; RTKs, receptor tyrosine kinase inhibitors; SAR, structure–activity relationship; SBDD, structure-based drug design; SCC, squamous cell carcinoma; SCNA, somatic copy number change; SHP2; SHP2, Src homology containing protein tyrosine phosphatase 2; STAT, signal transducers and activators of transcription; Selectivity; TIGIT, T-cell immunoglobulin and ITIM domain protein; TKIs, tyrosine kinase inhibitors; Tumor therapy; hERG, human ether-a-go-go-related gene.