Abstract：
Maternal embryonic leucine zipper kinase (MELK), a member of the AMP-related serine-threonine kinase family, has been involved in regulating many cellular events, and aberrant MELK expression is associated with tumorigenesis and malignant progression in various cancers. More and more studies have found that MELK plays an essential regulatory role in tumor multidrug resistance or radio resistance. MELK inhibitors can also improve drug resistance caused by a gene mutation. These findings remind us that MELK could be a chemo- or radio-sensitizing target. However, it has also been found that most experiments on MELK rely on non-selective RNAi and small molecule reagents, which makes the results questionable, and thus the development of selective MELK inhibitors is still necessary. In this review, we summarized the identified regulatory pathways of MELK in tumor resistance and reclassified MELK inhibitors from a structural perspective. In addition, we discovered the glycosylation modification site of the MELK protein and discussed the possibility of continuing to develop small molecule inhibitors targeting the glycosylation modification site. These provide new strategies for developing selective MELK inhibitors and understanding the essential biological role of MELK in cancer.
摘要：
母体胚胎亮氨酸拉链激酶(MELK),AMP相关丝氨酸-苏氨酸激酶家族的成员，参与调节许多细胞事件，MELK的异常表达与各种癌症的肿瘤发生和恶性进展有关。越来越多的研究发现,MELK在肿瘤多药耐药或放射耐药中起着至关重要的调控作用。MELK抑制剂还可以改善由基因突变引起的耐药性。这些发现提醒我们，MELK可能是化学或放射增敏靶标。然而,研究还发现，大多数MELK实验依赖于非选择性RNAi和小分子试剂，这使得结果值得怀疑，因此开发选择性MELK抑制剂仍然是必要的。在这次审查中,我们总结了MELK在肿瘤耐药中的调控途径,并从结构角度对MELK抑制剂进行了重新分类.此外,我们发现了MELK蛋白的糖基化修饰位点,并讨论了继续开发靶向糖基化修饰位点的小分子抑制剂的可能性.这些为开发选择性MELK抑制剂和理解MELK在癌症中的重要生物学作用提供了新的策略。
