Zhang Sheng, Zhang Zhong-Yin
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
Drug Discov Today. 2007 May;12(9-10):373-81. doi: 10.1016/j.drudis.2007.03.011. Epub 2007 Apr 6.
Protein tyrosine phosphatase 1B (PTP1B) is an effective target for the treatment of both type 2 diabetes and obesity; however, targeting PTP1B for drug discovery is challenging because of the highly conserved and positively charged active-site pocket. Tremendous progress has been made in the development of potent and selective PTP1B inhibitors that engage both the active site and no catalytic sites. Several strategies are being pursued to improve the pharmacological properties of PTP1B inhibitors. These new developments suggest that it is feasible to acquire PTP1B-based, small-molecule therapeutics with the requisite potency and selectivity. Future efforts will probably transform the potent and selective PTP1B inhibitors into orally available drugs with desirable physicochemical properties and in vivo efficacies.
蛋白酪氨酸磷酸酶1B（PTP1B）是治疗2型糖尿病和肥胖症的有效靶点；然而，由于其活性位点口袋高度保守且带正电荷，将PTP1B作为药物研发靶点具有挑战性。在开发既能结合活性位点又不结合催化位点的强效和选择性PTP1B抑制剂方面已经取得了巨大进展。目前正在探索多种策略来改善PTP1B抑制剂的药理特性。这些新进展表明，获得具有所需效力和选择性的基于PTP1B的小分子疗法是可行的。未来的努力可能会将强效和选择性PTP1B抑制剂转化为具有理想理化性质和体内疗效的口服药物。
