Encoded by PTPN11, the SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) is widely recognized as a carcinogenic phosphatase. As a promising anti-cancer drug target, SHP2 regulates many signaling pathways such as RAS-RAF-ERK, PI3K-AKT and JAK-STAT. Meanwhile, SHP2 plays a significant role in regulating immune cell function in the tumor microenvironment. Heretofore, five SHP2 allosteric inhibitors have been recruited in clinical studies for the treatment of cancer. Most recently, studies have proved the therapeutic potential of SHP2 inhibitor in overcoming drug resistance of kinase inhibitors and programmed cell death-1 (PD-1) blockade. Herein, we review the structure, function and small molecular inhibitors of SHP2, and highlight recent progress in overcoming drug resistance using SHP2 inhibitor. We hope this review would facilitate the future clinical development of SHP2 inhibitors.

由PTPN11编码, SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) 被广泛认为是一种致癌磷酸酶。作为一种很有前景的抗癌药物靶点，SHP2调节RAS-RAF-ERK、PI3K-AKT和JAK-STAT等多种信号通路。同时，SHP2在调节肿瘤微环境中的免疫细胞功能方面发挥着重要作用。迄今为止，已经在临床研究中招募了五种 SHP2 变构抑制剂来治疗癌症。最近，研究证明了 SHP2 抑制剂在克服激酶抑制剂的耐药性和程序性细胞死亡-1 (PD-1) 阻断方面的治疗潜力。在此，我们回顾了 SHP2 的结构、功能和小分子抑制剂，并重点介绍了使用 SHP2 抑制剂克服耐药性的最新进展。