Abstract：
The proviral integration for the Moloney murine leukemia virus (PIM) kinases, belonging to serine/threonine kinase family, have been found to be overexpressed in various types of cancers, such as prostate, breast, colon, endometrial, gastric, and pancreatic cancer. The three isoforms PIM kinases i.e., PIM1, PIM2, and PIM3 share a high degree of sequence and structural similarity and phosphorylate substrates controlling tumorigenic phenotypes like proliferation and cell survival. Targeting short-lived PIM kinases presents an intriguing strategy as in vivo knock-down studies result in non-lethal phenotypes, indicating that clinical inhibition of PIM might have fewer adverse effects. The ATP binding site (hinge region) possesses distinctive attributes, which led to the development of novel small molecule scaffolds that target either one or all three PIM isoforms. Machine learning and structure-based approaches have been at the forefront of developing novel and effective chemical therapeutics against PIM in preclinical and clinical settings, and none have yet received approval for cancer treatment. The stability of PIM isoforms is maintained by PIM kinase activity, which leads to resistance against PIM inhibitors and chemotherapy; thus, to overcome such effects, PIM proteolysis targeting chimeras (PROTACs) are now being developed that specifically degrade PIM proteins. In this review, we recapitulate an overview of the oncogenic functions of PIM kinases, their structure, function, and crucial signaling network in different types of cancer, and the potential of pharmacological small-molecule inhibitors. Further, our comprehensive review also provides valuable insights for developing novel antitumor drugs that specifically target PIM kinases in the future. In conclusion, we provide insights into the benefits of degrading PIM kinases as opposed to blocking their catalytic activity to address the oncogenic potential of PIM kinases.
摘要：
莫洛尼鼠白血病病毒（PIM）激酶的前整合，属于丝氨酸/苏氨酸激酶家族，已经发现在各种类型的癌症中过度表达，比如前列腺,乳房,结肠,子宫内膜,胃,还有胰腺癌.三种同工型PIM激酶，即，PIM1，PIM2和PIM3共享高度的序列和结构相似性，并磷酸化控制肿瘤表型如增殖和细胞存活的底物。靶向短寿命的PIM激酶提出了一个有趣的策略，因为体内敲除研究导致非致死表型。表明PIM的临床抑制可能具有较少的不良反应。ATP结合位点（铰链区）具有独特的属性，这导致了针对一种或所有三种PIM同工型的新型小分子支架的开发。机器学习和基于结构的方法一直处于在临床前和临床环境中开发针对PIM的新型有效化学疗法的最前沿。还没有人获得癌症治疗的批准。PIM同工型的稳定性由PIM激酶活性维持,这导致对PIM抑制剂和化疗的耐药性；因此，为了克服这种影响，目前正在开发特异性降解PIM蛋白的PIM蛋白水解靶向嵌合体(PROTACs)。在这次审查中,我们概述了PIM激酶的致癌功能，他们的结构,函数,以及不同类型癌症的关键信号网络，和药理学小分子抑制剂的潜力。Further,我们的全面综述还为未来开发特异性靶向PIM激酶的新型抗肿瘤药物提供了有价值的见解.总之,我们提供了有关降解PIM激酶的好处的见解，而不是阻断其催化活性，以解决PIM激酶的致癌潜力。
