College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
Vessel-Organ Interaction Research Center, Kyungpook National University, Daegu 41566, Republic of Korea.
Int J Mol Sci. 2023 Jan 4;24(2):953. doi: 10.3390/ijms24020953.
Autophagy is a cellular process that removes damaged components of cells and recycles them as biochemical building blocks. Autophagy can also be induced to protect cells in response to intra- and extracellular stresses, including damage to cellular components, nutrient deprivation, hypoxia, and pathogenic invasion. Dysregulation of autophagy has been attributed to various diseases. In particular, autophagy protects cancer cells by supporting tumor cell survival and the development of drug resistance. Understanding the pathophysiological mechanisms of autophagy in cancer has stimulated the research on discovery and development of specific inhibitors targeting various stages of autophagy. In recent years, Unc-51-like autophagy-activating kinase (ULK) inhibitors have become an attractive strategy to treat cancer. This review summarizes recent discoveries and developments in small-molecule ULK inhibitors and their potential as anticancer agents. We focused on structural features, interactions with binding sites, and biological effects of these inhibitors. Overall, this review will provide guidance for using ULK inhibitors as chemical probes for autophagy in various cancers and developing improved ULK inhibitors that would enhance therapeutic benefits in the clinic.
自噬是一种细胞过程，可清除细胞内受损的成分，并将其回收再利用为生化构建块。自噬也可以被诱导来保护细胞，以应对细胞内和细胞外的应激，包括细胞成分的损伤、营养缺乏、缺氧和病原体入侵。自噬的失调与各种疾病有关。特别是，自噬通过支持肿瘤细胞存活和耐药性的发展来保护癌细胞。了解自噬在癌症中的病理生理机制，激发了针对自噬各个阶段的特异性抑制剂的发现和开发。近年来，非典型卷曲螺旋激酶 1（Unc-51-like autophagy-activating kinase，ULK）抑制剂已成为治疗癌症的一种有吸引力的策略。本综述总结了小分子 ULK 抑制剂的最新发现和进展及其作为抗癌药物的潜力。我们重点介绍了这些抑制剂的结构特征、与结合位点的相互作用以及生物学效应。总的来说，本综述将为在各种癌症中使用 ULK 抑制剂作为自噬的化学探针，并开发出能在临床上增强治疗效果的改进型 ULK 抑制剂提供指导。
