Department of Chemistry and Biochemistry, University of Texas at Austin, TX, USA.
FEBS J. 2013 Oct;280(19):4739-60. doi: 10.1111/febs.12481. Epub 2013 Sep 5.
Protein phosphatases, as the counterpart to protein kinases, are essential for homeostatic balance of cell signaling. Small chemical compounds that modulate the specific activity of phosphatases can be powerful tools to elucidate the biological functions of these enzymes. More importantly, many phosphatases are central players in the development of pathological pathways where inactivation can reverse or delay the onset of human diseases. Therefore, potent inhibitors for such phosphatases can be of great therapeutic benefit. In contrast to the seemingly identical enzymatic mechanism and structural characterization of eukaryotic protein kinases, protein phosphatases evolved from diverse ancestors, resulting in different domain architectures, reaction mechanisms and active site properties. In this review, we discuss for each family of serine/threonine protein phosphatases their involvement in biological processes and corresponding strategies for small chemical intervention. Recent advances in modern drug discovery technologies have markedly facilitated the identification of selective inhibitors for some members of the phosphatase family. Furthermore, the rapid growth in knowledge about structure-activity relationships related to possible new drug targets has aided the discovery of natural product inhibitors for the phosphatase family. This review summarizes the current state of investigation of the small molecules that regulate the function of serine/threonine phosphatases, the challenges presented and also strategies to overcome these obstacles.
蛋白磷酸酶作为蛋白激酶的对应物，对于细胞信号转导的内稳态平衡至关重要。调节磷酸酶特异性活性的小分子化合物可以成为阐明这些酶生物学功能的有力工具。更重要的是，许多磷酸酶是病理性途径的核心参与者，其失活可以逆转或延迟人类疾病的发作。因此，针对这些磷酸酶的有效抑制剂可能具有巨大的治疗益处。与真核蛋白激酶看似相同的酶促机制和结构特征不同，蛋白磷酸酶由不同的祖先进化而来，导致不同的结构域架构、反应机制和活性位点特性。在这篇综述中，我们讨论了每种丝氨酸/苏氨酸蛋白磷酸酶家族在生物过程中的参与情况，以及针对这些酶进行小分子干预的相应策略。现代药物发现技术的最新进展显著促进了一些磷酸酶家族成员的选择性抑制剂的鉴定。此外，与可能的新药物靶点相关的结构-活性关系的快速增长，也有助于发现磷酸酶家族的天然产物抑制剂。本综述总结了目前对调节丝氨酸/苏氨酸磷酸酶功能的小分子的研究现状、所面临的挑战以及克服这些障碍的策略。
