Cancer Therapy and Research Center, Institute for Drug Development, University of Texas Health Science Center at San Antonio, 7979 Wurzbach Road, San Antonio, TX 78229, USA.
Curr Drug Targets. 2011 Dec;12(14):2059-66. doi: 10.2174/138945011798829447.
The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to cancer development and progression. They were first recognized as pro-viral integration sites for the Moloney Murine Leukemia virus. Unlike other kinases, they possess a hinge region which creates a unique binding pocket for ATP. Absence of a regulatory domain means that these proteins are constitutively active once transcribed. Pim kinases are critical downstream effectors of the ABL (ableson), JAK2 (janus kinase 2), and Flt-3 (FMS related tyrosine kinase 1) oncogenes and are required by them to drive tumorigenesis. Recent investigations have established that the Pim kinases function as effective inhibitors of apoptosis and when overexpressed, produce resistance to the mTOR (mammalian target of rapamycin) inhibitor, rapamycin . Overexpression of the PIM kinases has been reported in several hematological and solid tumors (PIM 1), myeloma, lymphoma, leukemia (PIM 2) and adenocarcinomas (PIM 3). As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Novel small molecule inhibitors of the human Pim kinases have been designed and are currently undergoing preclinical evaluation.
Pim 激酶家族有三个成员，是丝氨酸/苏氨酸激酶，能够调节多种信号通路，这些信号通路对于癌症的发生和发展至关重要。它们首次被认为是莫洛尼鼠白血病病毒的前病毒整合位点。与其他激酶不同，它们具有铰链区，能够为 ATP 创造独特的结合口袋。由于缺乏调节结构域，这些蛋白在转录后会一直保持活性。Pim 激酶是 ABL（abl 基因）、JAK2（janus 激酶 2）和 Flt-3（FMS 相关酪氨酸激酶 1）致癌基因的关键下游效应因子，它们是肿瘤发生所必需的。最近的研究表明，Pim 激酶能够有效地抑制细胞凋亡，并且当过度表达时，会对 mTOR（雷帕霉素靶蛋白）抑制剂 rapamycin 产生耐药性。在几种血液系统肿瘤和实体瘤（Pim 1）、骨髓瘤、淋巴瘤、白血病（Pim 2）和腺癌（Pim 3）中都发现 Pim 激酶过表达。因此，Pim 激酶是癌症治疗中药物抑制的一个非常有吸引力的靶点。已经设计出了针对人 Pim 激酶的新型小分子抑制剂，目前正在进行临床前评估。
