Jingwei Wu, Huan Zhang, Guilong Zhao* and Runling Wang* Pages 3825 - 3842 ( 18 )
Srchomology-2-domain-containing PTP 2 (SHP2) is a nonreceptor phosphatase encoded by the PTPN11 gene. Over expression of SHP2 is associated with various human diseases, such as Noonan syndrome, LEOPARD syndrome, and cancers. To overcome the shortcomings of existing orthosteric inhibitors, novel inhibitors targeting the allosteric site of SHP2 with high selectivity and low toxicity are under development. This paper reviews allosteric inhibitors of SHP2 published in patents from 2015 to 2020. The molecules are classified according to the chemical structure of the central core. SHP2 has long been considered as an ‘undruggable’ protein. Fortunately, a critical breakthrough was made by researchers from Novartis AG Ltd., who identified SHP099 as a highly potent, selective, soluble, and orally bioavailable SHP2 allosteric inhibitor. Currently, there are several allosteric inhibitors of SHP2 in clinical development. However, drug resistance is still a major challenge. The combination of SHP2 allosteric inhibitors and immunotherapy drugs or molecular targeted drugs is emerging as a promising therapeutic strategy against drug resistance.
SHP2 inhibitor, PTPN11 gene, allosteric, cancer, combination therapy, clinical trial.
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, No. 22, Qixiangtai Road, Heping District, Tianjin 300070, Department of Pharmacy, Tianjin Medical University General Hospital, Tianjin 300052, The Institute of Drug Discovery and Development, Chinese Academy of Sciences, Zhongshan 528400, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, No. 22, Qixiangtai Road, Heping District, Tianjin 300070