Rout Ajaya Kumar, Dehury Budheswar, Parida Satya Narayan, Rout Sushree Swati, Jena Rajkumar, Kaushik Neha, Kaushik Nagendra Kumar, Pradhan Sukanta Kumar, Sahoo Chita Ranjan, Singh Ashok Kumar, Arya Meenakshi, Behera Bijay Kumar
Rani Lakshmi Bai Central Agricultural University, Jhansi-284003, Uttar Pradesh, India.
Department of Bioinformatics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal-576104, India.
Int J Biol Macromol. 2024 Jun;270(Pt 1):132030. doi: 10.1016/j.ijbiomac.2024.132030. Epub 2024 May 3.
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.
莫洛尼鼠白血病病毒（PIM）激酶属于丝氨酸/苏氨酸激酶家族，其前病毒整合已被发现于多种类型的癌症中过度表达，如前列腺癌、乳腺癌、结肠癌、子宫内膜癌、胃癌和胰腺癌。PIM激酶的三种同工型，即PIM1、PIM2和PIM3，具有高度的序列和结构相似性，并磷酸化控制肿瘤发生表型（如增殖和细胞存活）的底物。靶向半衰期短的PIM激酶是一种引人入胜的策略，因为体内敲低研究导致非致死表型，这表明临床抑制PIM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前沿，且尚无一种疗法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抑制剂和化疗的抗性；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蛋白酶靶向嵌合体（PROTAC）。在本综述中，我们概述了PIM激酶的致癌功能、其在不同类型癌症中的结构、功能和关键信号网络，以及药理学小分子抑制剂的潜力。此外，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，我们深入探讨了降解PIM激酶相对于阻断其催化活性以应对PIM激酶致癌潜力的益处。
