作者: Jeong, Kwiwan ; Choi, Dong Kyu ; Bae, Ji-Eun ; Kim, Seong Hyun ; So, Jun Hee ; Park, Daeun ; Jo, Doo Sin ; Park, Na Yeon ; Lee, Jae Man ; Cho, Dong-Hyung ; Kim, Yong Hwan ; Kim, Joon Bum

Autophagy-mediated organelle quality control is vital for cellular homeostasis. However, the mechanisms underlying selective autophagy of peroxisomes, known as pexophagy, are less well understood than those of other organelles, such as mitochondria. In this study, we screened a phosphatase inhibitor library using a cell-based system and identified several potent pexophagy inducers, including ZLDI-8, a known inhibitor of lymphoid-specific tyrosine phosphatase. Notably, treatment with ZLDI-8 selectively induces the loss of peroxisomes without affecting other organelles, such as mitochondria, the endoplasmic reticulum, or the Golgi apparatus. The peroxisome loss induced by ZLDI-8 was significantly blocked in ATG5-knockout HeLa cells, confirming its dependence on autophagy. We further found that ZLDI-8 treatment increases both cellular and peroxisomal reactive oxygen species (ROS), which were effectively scavenged by N-acetylcysteine (NAC). The increase in peroxisomal ROS leads to the activation of ATM kinase and the dephosphorylation of TFEB. Moreover, ROS scavenging prevents all of these processes. Taken together, these findings demonstrate that ZLDI-8 induces pexophagy through a mechanism involving peroxisomal ROS-mediated activation of TFEB and ATM. This study provides valuable insights into the molecular mechanisms regulating selective peroxisome degradation and potential therapeutic strategies for targeting pexophagy.

2025-04-01·BIOORGANIC CHEMISTRY

Discovery and evaluation of novel Benzohydroxamic acid-indole derivatives as dual inhibitors of ADAM17 and HDAC2 with antitumor activity

Article

作者: Wang, Ziyi ; Ren, Tianshu ; Jiang, Muxuan ; Sun, Yuzhu ; Chen, Di ; Hou, Shanbo ; Song, Aigang ; Qi, Yiming ; Xun, Fanghua ; Zhao, Qingchun ; Wang, Chengkang ; Song, Xiaoxuan ; Tong, Xin ; Zhang, Yingshi ; Gao, Huiyuan ; Liu, Wenwu ; Yang, Kaisi

Hepatocellular carcinoma (HCC) has garnered significant attention from researchers due to its high recurrence rate and invasive characteristics. The design of drugs with dual-target combined effects represents a promising strategy in cancer treatment. Our observations suggest that ADAM17 and HDAC may inhibit the unfavorable prognostic signaling pathway Notch1 in HCC through distinct mechanisms, thereby suppressing tumor cell proliferation and metastasis. Consequently, this study utilized the ADAM17 inhibitor ZLDI-8 as a lead compound and developed a series of dual ADAM17/HDAC2 inhibitors by integrating strategies such as backbone leaping and pharmacophore fusion. We assessed the anti-hepatocellular carcinoma activity of these compounds, focusing on their anti-proliferative, pro-apoptotic, and anti-metastatic properties. Notably, ZSNI-21 effectively inhibited the proliferation of Bel-7402 cells and demonstrated significant anti-metastatic capabilities against HCC-LM3 cells, with its targeting confirmed. Additionally, its in vivo safety was validated. To date, there have been no reports on dual ADAM17/HDAC2 inhibitors, marking this as a novel endeavor.

2024-05-01·Pharmacological research

The ADAM17 inhibitor ZLDI-8 sensitized hepatocellular carcinoma cells to sorafenib through Notch1-integrin β-talk

Article

作者: Xu, Chang ; Yang, Kaisi ; Song, Aigang ; Zhang, Weige ; Hou, Shanbo ; Gao, Xudong ; Zhang, Yingshi ; Geng, Hefeng ; Zhao, Qingchun ; Huang, Yaoguang ; Ren, Tianshu

ZLDI-8 is an A disintegrin and metalloproteinase domain 17 (ADAM17) inhibitor that suppresses the shedding of Notch1 to the Notch1 intracellular domain (NICD). In previous studies, we found that ZLDI-8 was able to sensitize HCC to sorafenib, but the mechanism of action remains unclear. The sensitizing effects of ZLDI-8 were tested both in vitro and in vivo. EMT-related factors, sorafenib sensitivity-related proteins and ECM-related gene expression were assessed using immunohistochemistry, RTPCR and Western blotting. Knockdown assays were conducted to determine the relationship between the Notch and Integrin pathways. CoIP assays, nuclear and cytoplasmic fractionation and immunofluorescence colocalization were applied to explore the interaction between the Notch and Integrin pathways. Appropriate statistical analysis methods were used to assess the significance of the experimental results and to ensure the scientific validity and reliability of the experimental design. We found that ECM- and EMT-related proteins were downregulated after ZLDI-8 treatment (P<0.05). ZLDI-8 significantly downregulated Integrinβ1 and Integrinβ3 in HCC in vitro and in vivo (P<0.05), possibly through Foxc2-dependent regulation. Mechanistically, interfering with the expression of both Integrin-linked kinase (ILK) and the NICD may downregulate the expression of proteins targeted by sorafenib, thereby sensitizing cells to sorafenib. The retroregulation of Integrinβ by ILK may occur through the interaction between the NICD and ILK and may be the result of the translocation of the complexus. Our study indicates that blocking the Notch pathway may affect Integrinβ through crosstalk between the Notch1 and Integrinβ/ILK signaling pathways, thus providing a potential therapeutic strategy for HCC.

100 项与 ZLDI-8 相关的药物交易

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