Src同源2（SH2）结构域含有酪氨酸磷酸酶-2（SHP2）是细胞周期中的一个重要调控因子，并且其活化突变在各种癌症的发展中起着重要作用，使其成为一种重要的抗肿瘤药物靶点。由于SHP2的活性位点具有高度保守的氨基酸序列和阳性电荷性质，因此很难发现对SHP2催化位点具有高亲和力和足够细胞渗透性的抑制剂，因此被认为是“难药化”的靶点。然而，异位调节机制的发现为将“难药化”靶点转化为“易药化”靶点提供了新的机会。鉴于原位抑制剂的局限性，SHP2异位抑制剂已成为更为选择性和安全的研究方向。在本文综述中，我们阐明了SHP2的致癌机制，并总结了SHP2异位抑制剂的发现方法，为SHP2异位抑制剂的设计和改进提供了新的策略。© 2023 Wiley Periodicals LLC.

Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) is a key regulatory factor in the cell cycle and its activating mutations play an important role in the development of various cancers, making it an important target for antitumor drugs. Due to the highly conserved amino acid sequence and positively charged nature of the active site of SHP2, it is difficult to discover inhibitors with high affinity for the catalytic site of SHP2 and sufficient cell permeability, making it considered an "undruggable" target. However, the discovery of allosteric regulation mechanisms provides new opportunities for transforming undruggable targets into druggable ones. Given the limitations of orthosteric inhibitors, SHP2 allosteric inhibitors have become a more selective and safer research direction. In this review, we elucidate the oncogenic mechanism of SHP2 and summarize the discovery methods of SHP2 allosteric inhibitors, providing new strategies for the design and improvement of SHP2 allosteric inhibitors.© 2023 Wiley Periodicals LLC.