Dysregulation of intracellular signaling pathways is a key attribute of diseases associated with chronic inflammation, including cancer. Mitogen activated protein kinases have emerged as critical conduits of intracellular signal transmission, yet due to their ubiquitous roles in cellular processes, their direct inhibition may lead to undesired effects, thus limiting their usefulness as therapeutic targets. Mixed lineage kinases (MLKs) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that interact with scaffolding proteins and function upstream of p38, JNK, ERK, and NF-kappaB to mediate diverse cellular signals. Studies involving gene silencing, genetically engineered mouse models, and small molecule inhibitors suggest that MLKs are critical in tumor progression as well as in inflammatory processes. Recent advances indicate that they may be useful targets in some types of cancer and in diseases driven by chronic inflammation including neurodegenerative diseases and metabolic diseases such as nonalcoholic steatohepatitis. This review describes existing MLK inhibitors, the roles of MLKs in various aspects of tumor progression and in the control of inflammatory processes, and the potential for therapeutic targeting of MLKs.

中文翻译：

---

靶向混合谱系激酶在癌症和炎症中的治疗潜力。

细胞内信号传导途径的失调是与包括炎症在内的慢性炎症有关的疾病的关键属性。丝裂原活化的蛋白激酶已经作为细胞内信号传递的关键管道出现，但是由于它们在细胞过程中普遍存在，其直接抑制作用可能导致不良作用，从而限制了其作为治疗靶标的用途。混合谱系激酶（MLK）是促细胞分裂素激活的蛋白激酶激酶（MAP3K），与支架蛋白相互作用，在p38，JNK，ERK和NF-κB的上游起作用，以介导多种细胞信号。涉及基因沉默，基因工程小鼠模型和小分子抑制剂的研究表明，MLK对肿瘤进展以及炎症过程至关重要。最近的进展表明，它们在某些类型的癌症和慢性炎症驱动的疾病（包括神经退行性疾病和代谢性疾病，例如非酒精性脂肪性肝炎）中可能是有用的靶标。这篇综述描述了现有的MLK抑制剂，MLK在肿瘤进展的各个方面以及在炎症过程控制中的作用以及治疗性靶向MLK的潜力。