自从发现酪氨酸磷酸化是癌症信号调节的关键调节因子以来，调节细胞磷酸酪氨酸水平的蛋白质已经迅速成为治疗干预的目标。非受体蛋白酪氨酸磷酸酶（PTP），由PTPN11基因编码的"SHP2"，将生长因子受体的磷酸酪氨酸信号整合到RAS/RAF/ERK通路中，并且在调节细胞发育和致癌转化的过程中起到中心作用。SHP2表达或活性的失调与肿瘤发生和发育缺陷有关。尽管是一个引人注目的抗癌靶点，由于其保守的催化PTP结构域逃避药物研发，长期以来被认为SHP2是"难以药物靶向"的。最近，通过发现能够有效抑制其内在变构作用的小分子，SHP2已经从"难以药物靶向的诅咒"中崛起。SHP2独特的结构域排列和构象允许基于对蛋白质的非催化位点的巧妙靶向开发出一种全新的抑制剂发展范式。在本综述中，我们总结了SHP2的生物学功能、信号传导特性、结构属性、内在变构性和抑制剂。版权所有© 2023。Elsevier Inc.出版。

Since the discovery of tyrosine phosphorylation being a critical modulator of cancer signaling, proteins regulating phosphotyrosine levels in cells have fast become targets of therapeutic intervention. The nonreceptor protein tyrosine phosphatase (PTP) coded by the PTPN11 gene "SHP2" integrates phosphotyrosine signaling from growth factor receptors into the RAS/RAF/ERK pathway and is centrally positioned in processes regulating cell development and oncogenic transformation. Dysregulation of SHP2 expression or activity is linked to tumorigenesis and developmental defects. Even as a compelling anti-cancer target, SHP2 was considered "undruggable" for a long time owing to its conserved catalytic PTP domain that evaded drug development. Recently, SHP2 has risen from the "undruggable curse" with the discovery of small molecules that manipulate its intrinsic allostery for effective inhibition. SHP2's unique domain arrangement and conformation(s) allow for a truly novel paradigm of inhibitor development relying on skillful targeting of noncatalytic sites on proteins. In this review we summarize the biological functions, signaling properties, structural attributes, allostery and inhibitors of SHP2.Copyright © 2023. Published by Elsevier Inc.