Lee Seokjoon, Wang Qian
Department of Basic Science, Kwandong University College of Medicine, Gangneung 210-701, South Korea.
Med Res Rev. 2007 Jul;27(4):553-73. doi: 10.1002/med.20079.
Protein tyrosine phosphatases (PTPs), a large family of signaling enzymes, play essential roles in intracellular signal transduction by regulating the cellular level of tyrosine phosphorylation to control cell growth and differentiation, metabolism, cell migration, gene transcription, ion-channel activity, immune response, cell apoptosis, and bone development. Among all PTPs, protein tyrosine phosphatase 1B (PTP1B) plays a seminal role in cellular signaling and in many human diseases, including cancer, diabetes, and obesity. Therefore, small molecular inhibitors of PTP1B can be promising drug candidates. Because of the structural homologies in many families of PTPs, it is a challenging task to find inhibitors specific to each PTP. Recent studies suggested that secondary binding pockets or peripheral binding sites around the conserved active site should be exploited to design novel potent and selective PTP1B inhibitors. In this review, we discuss the structural and biological features of small molecular PTP1B-specific inhibitors, with particular emphasis on small molecular inhibitors targeting PTP1B over the other PTPs that have been synthesized in the past 4 years.
蛋白酪氨酸磷酸酶（PTPs）是一大类信号酶，通过调节细胞内酪氨酸磷酸化水平来控制细胞生长和分化、代谢、细胞迁移、基因转录、离子通道活性、免疫反应、细胞凋亡及骨骼发育，在细胞内信号转导中发挥着至关重要的作用。在所有PTPs中，蛋白酪氨酸磷酸酶1B（PTP1B）在细胞信号传导以及包括癌症、糖尿病和肥胖症在内的许多人类疾病中起着关键作用。因此，PTP1B的小分子抑制剂有望成为有潜力的候选药物。由于许多PTP家族存在结构同源性，找到针对每种PTP的特异性抑制剂是一项具有挑战性的任务。最近的研究表明，应利用保守活性位点周围的二级结合口袋或周边结合位点来设计新型强效且选择性的PTP1B抑制剂。在本综述中，我们讨论了小分子PTP1B特异性抑制剂的结构和生物学特性，特别强调了在过去4年中合成的、针对PTP1B而非其他PTP的小分子抑制剂。
