Philipps University Marburg, Institute for Surgical Research, Baldingerstrasse, Marburg, 35033, Germany.
Expert Opin Investig Drugs. 2012 Apr;21(4):425-36. doi: 10.1517/13543784.2012.668527. Epub 2012 Mar 4.
Inhibition of protein kinases has become a standard of modern clinical oncology. PIM1 belongs to a novel class of serine/threonine kinases with distinct molecular and biochemical features regulating various oncogenic pathways, for example hypoxia response, cell cycle progression and apoptosis resistance. PIM1 is overexpressed in human cancer diseases and has been associated with metastasis and overall treatment response; in experimental models, inhibition of PIM1 suppressed cell proliferation and migration, induced apoptotic cell death and synergized with other chemotherapeutic agents.
A PubMed literature search was performed to review the currently available data on PIM1 expression, regulation and targets; its implication in different types of cancer and its impact on prognosis are described. We present ATP-competitive PIM1 inhibitors and the state of the art of PIM1 inhibitor design. Finally, we highlight the development of the unusual class of highly selective and potent organometallic PIM1 inhibitors.
As PIM1 possesses oncogenic functions and is overexpressed in various kinds of cancer diseases, its inhibition provides a new option in cancer therapy. Based on the ability of highly selective organometallic PIM1 inhibitors, promising in vivo applicability is expected.
蛋白激酶抑制已成为现代临床肿瘤学的标准。PIM1 属于一种新型丝氨酸/苏氨酸激酶，具有独特的分子和生化特征，可调节各种致癌途径，例如缺氧反应、细胞周期进展和凋亡抵抗。PIM1 在人类癌症中过度表达，并与转移和整体治疗反应相关；在实验模型中，抑制 PIM1 可抑制细胞增殖和迁移，诱导细胞凋亡死亡，并与其他化疗药物协同作用。
对 PubMed 文献进行了检索，以综述目前关于 PIM1 表达、调节和靶点的可用数据；描述了其在不同类型癌症中的作用及其对预后的影响。我们介绍了 ATP 竞争性 PIM1 抑制剂和 PIM1 抑制剂设计的最新进展。最后，我们强调了高度选择性和有效的有机金属 PIM1 抑制剂这一不寻常类别抑制剂的发展。
由于 PIM1 具有致癌功能，并且在各种癌症中过度表达，因此抑制 PIM1 为癌症治疗提供了新的选择。基于高度选择性有机金属 PIM1 抑制剂的能力，预计其具有有前景的体内适用性。
