Jiang Zhong-Xing, Zhang Zhong-Yin
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Cancer Metastasis Rev. 2008 Jun;27(2):263-72. doi: 10.1007/s10555-008-9113-3.
Protein tyrosine phosphorylation plays a major role in cellular signaling. The level of tyrosine phosphorylation is controlled by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Disturbance of the normal balance between PTK and PTP activity results in aberrant tyrosine phosphorylation, which has been linked to the etiology of several human diseases, including cancer. A number of PTPs have been implicated in oncogenesis and tumor progression and therefore are potential drug targets for cancer chemotherapy. These include PTP1B, which may augment signaling downstream of HER2/Neu; SHP2, which is the first oncogene in the PTP superfamily and is essential for growth factor-mediated signaling; the Cdc25 phosphatases, which are positive regulators of cell cycle progression; and the phosphatase of regenerating liver (PRL) phosphatases, which promote tumor metastases. As PTPs have emerged as drug targets for cancer, a number of strategies are currently been explored for the identification of various classes of PTP inhibitors. These efforts have resulted many potent, and in some cases selective, inhibitors for PTP1B, SHP2, Cdc25 and PRL phosphatases. Structural information derived from these compounds serves as a solid foundation upon which novel anti-cancer agents targeted to these PTPs can be developed.
蛋白质酪氨酸磷酸化在细胞信号传导中起主要作用。酪氨酸磷酸化水平由蛋白质酪氨酸激酶（PTK）和蛋白质酪氨酸磷酸酶（PTP）控制。PTK和PTP活性之间正常平衡的紊乱会导致异常的酪氨酸磷酸化，这与包括癌症在内的几种人类疾病的病因有关。许多PTP与肿瘤发生和肿瘤进展有关，因此是癌症化疗的潜在药物靶点。这些包括可能增强HER2/Neu下游信号传导的PTP1B；作为PTP超家族中的首个癌基因且对生长因子介导的信号传导至关重要的SHP2；作为细胞周期进程正调控因子的Cdc25磷酸酶；以及促进肿瘤转移的再生肝磷酸酶（PRL）。随着PTP已成为癌症的药物靶点，目前正在探索多种策略来鉴定各类PTP抑制剂。这些努力已产生了许多针对PTP1B、SHP2、Cdc25和PRL磷酸酶的强效且在某些情况下具有选择性的抑制剂。从这些化合物获得的结构信息为开发靶向这些PTP的新型抗癌药物奠定了坚实基础。
