1. Tyrosine phosphatase SHP2 inhibitors in tumor-targeted therapies
- Author
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Xiao-Feng Xiong, Yang Sun, Xue Ping Chen, Zhendong Song, Ziyang Xu, Yang Ge, and Meijing Wang
- Subjects
PDAC, pancreatic ductal adenocarcinoma ,STAT, signal transducers and activators of transcription ,RAS, rat sarcoma protein ,Protein tyrosine phosphatase ,Review ,TIGIT, T-cell immunoglobulin and ITIM domain protein ,SCC, squamous cell carcinoma ,B-ALL, B-cell acute lymphoblastic leukemia ,SCNA, somatic copy number change ,0302 clinical medicine ,KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ,Selectivity ,CTLA-4, cytotoxic T lymphocyte-associated antigen-4 ,General Pharmacology, Toxicology and Pharmaceutics ,Tyrosine ,GAB2, Grb2-associated binding protein-2 ,PD-1/PDL-1, programmed cell death protein-1/programmed death ligand-1 ,AML, acute myeloid leukemia ,0303 health sciences ,PTK, protein tyrosine kinase ,Chemistry ,SHP2, Src homology containing protein tyrosine phosphatase 2 ,TKIs, tyrosine kinase inhibitors ,030220 oncology & carcinogenesis ,Tumor therapy ,JAK, Janus kinase ,BTLA, B and T lymphocyte attenuator ,PTP, protein tyrosine phosphatase ,RTKs, receptor tyrosine kinase inhibitors ,Proto-oncogene tyrosine-protein kinase Src ,Allosteric inhibitor ,Phosphatase ,Allosteric regulation ,CSF-1, colony stimulating factor-1 ,Tumor targeted ,03 medical and health sciences ,PI3K, phosphatidylinositol 3 kinase ,TYROSINE PHOSPHATASE SHP2 ,SAR, structure–activity relationship ,ERK1/2, extracelluar signal-regulated kinase 1/2 ,SBDD, structure-based drug design ,GRB2, growth factor receptor-bound protein 2 ,PDX, patient-derived xenograft ,030304 developmental biology ,FLT3, Fms-like tyrosine kinase-3 ,ALK, anaplastic lymphoma kinase ,lcsh:RM1-950 ,Bioavailability ,EGFR, epidermal growth factor receptor ,CADD, computer aided drug design ,lcsh:Therapeutics. Pharmacology ,HGF/SF, hepatocyte growth factor/scatter factor ,NLRP3, NLR family, pyrin domain containing protein 3 ,HER2, human epidermal growth factor receptor-2 ,Cancer research ,SHP2 ,MAPK, mitogen-activated protein kinase ,hERG, human ether-a-go-go-related gene - 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., Graphical abstract This review summarized the development and structure–activity relationship studies of the small-molecule SHP2 inhibitors, as well as the application of SHP2 inhibitors for tumor therapies. The discovery and development of each type inhibitors were discussed based on their chemotypes, activity, selectivity and cocrystal structures.Image 1
- Published
- 2020