Donghui Sun, Li Kang, Xuwen Chen, Jian Xue, Xin Wu, Jiemin Wong, Qinghua Wei, Shunying Liu
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引用次数: 0
摘要
骨肉瘤(Osteosarcoma,OS)是一种罕见的恶性肿瘤,在过去 50 年中主要影响儿童和青少年。骨肉瘤的基因组具有高度复杂性,这给抗骨肉瘤靶点的确定带来了巨大挑战。迄今为止,治疗 OS 的高效靶点尚未在临床实践中得到验证。在我们之前通过表型筛选寻找治疗 OS 的药物时,我们发现噻唑啉酮衍生物 (R)-8i 是一种在 MNNG/HOS 细胞和体内对 OS 有效的选择性抑制剂。然而,(R)-8i 的作用机制和特定分子靶点仍不清楚。在本研究中,我们设计并合成了基于先导化合物(R)-8i的光交联探针,并利用基于活性的蛋白质分析策略确定了DDX5作为潜在的靶蛋白。包括 Western 印迹、shRNA 敲除实验、细胞集落形成、伤口愈合实验和细胞热转移实验在内的进一步实验证明,(R)-8i 能与 DDX5 结合并诱导其降解,从而通过 PI3K-AKT-mTOR 信号通路影响细胞增殖和迁移。研究表明,DDX5是治疗OS的潜在治疗靶点。
Identification of DDX5 as a Potential Therapeutic Target of Osteosarcoma Using Thiazolone Probes.
Osteosarcoma (OS) is a rare malignant tumor that has predominantly affected children and adolescents in the past 50 years. The genomes of OS tumors exhibit a high degree of complexity, which leads to the great challenge of target identification for anti-OS. To date, no efficient therapeutic target for the treatment of OS has been validated in clinical practice. In our previous drug hunting for the treatment of OS by phenotypic screening, we found that thiazolone derivate (R)-8i was an effective and selective inhibitor against OS in MNNG/HOS cells and in vivo. However, the mechanism of action and specific molecular targets of (R)-8i remain unclear. In this study, we design and synthesize the photo-cross-linking probes based on the lead compound (R)-8i and identify DDX5 as a potential target protein using an activity-based protein profiling strategy. Further experiments including Western blot, shRNA knockdown experiments, cell colony formation, wound healing assays, and cellular thermal shift assays support that (R)-8i binds to DDX5 and induces its degradation, which affect cell proliferation and migration through the PI3K-AKT-mTOR signaling pathway. The research shows that DDX5 is a potential therapeutic target for the treatment of OS.
期刊介绍:
ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology.
The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies.
We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.