Department of Cell and Molecular Pharmacology & Experimental Therapeutics, College of Medicine, Medical University of South Carolina, Charleston, SC, United States.
Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC, United States.
Adv Cancer Res. 2023;160:17-60. doi: 10.1016/bs.acr.2023.03.003. Epub 2023 Apr 17.
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.
自从发现酪氨酸磷酸化是癌症信号的关键调节剂以来，调节细胞中磷酸酪氨酸水平的蛋白质迅速成为治疗干预的靶点。由 PTPN11 基因编码的非受体蛋白酪氨酸磷酸酶（PTP）“SHP2”将生长因子受体的磷酸酪氨酸信号整合到 RAS/RAF/ERK 途径中，并在调节细胞发育和致癌转化的过程中处于中心位置。SHP2 表达或活性的失调与肿瘤发生和发育缺陷有关。即使作为一个有吸引力的抗癌靶点，SHP2 也因其保守的催化 PTP 结构域而长期被认为是“不可成药的”，因为该结构域逃避了药物开发。最近，随着小分子的发现，能够操纵其内在变构以实现有效抑制，SHP2 已经摆脱了“不可成药的诅咒”。SHP2 独特的结构排列和构象允许基于对蛋白质非催化位点的巧妙靶向，开发出真正新颖的抑制剂范例。在这篇综述中，我们总结了 SHP2 的生物学功能、信号特性、结构属性、变构和抑制剂。
