LF-3

Colorectal cancer (CRC) has been becoming one of the most common causes of cancer mortality worldwide. Accumulating studies suggest that the progressive up-regulation of Wnt/β-catenin signaling is a crucial hallmark of CRC, and suppressing it is a promising strategy to treat CRC. Herein, we reported our latest efforts in the discovery of novel fused tetrahydroisoquinoline derivatives with good anti-CRC activities by screening our in-house berberine-like library and further structure-activity relationship (SAR) studies, in which we identified compound 10 is a potent lead compound with significant antiproliferation potencies. By the biotinylated probe and LC-MS/MS study, Hsp90 was identified as its molecular target, which is a fully different mechanism of action from what we reported before. Further studies showed compound 10 directly engaged the N-terminal site of Hsp90 and promoted the degradation of β-catenin, thereby suppressing the Wnt/β-catenin signaling. More importantly, compound 10 exhibits favorable pharmacokinetic parameters and significant anti-tumor efficacies in the HCT116 xenograft model. Taken together, this study furnished the discovery of candidate drug compound 10 possessing a novel fused tetrahydroisoquinoline scaffold with excellent in vitro and in vivo anti-CRC activities by targeting Hsp90 to disturb Wnt/β-catenin signaling pathway, which lay a foundation for discovering more effective CRC-targeted therapies.

This study was designed to explore the influence of myelin protein zero-like protein 1 (MPZL1) on the stem-like properties of cancer cells and the underlying mechanism in lung adenocarcinoma. Real-time quantitative polymerase chain reaction (RT-qPCR) was utilized to evaluate mRNA expression level. CCK8, wound healing, and transwell assays were applied to assess cell proliferation, migration, and invasion. Tumorsphere-formation assay was utilized to assess cancer stem cell-like properties. LF3 was used to block the β-catenin/Transcription factor 4 (TCF-4) signaling. Xenograft nude mouse model was conducted; tumor weight and volume were recorded. Western blot assay was utilized to detect the expression levels of CD44, CD133, β-catenin, TCF-4, and MPZL1. Following MPZL1 knockdown, the mRNA expression levels of MPZL1, β-catenin, and TCF-4 were inhibited, while the mRNA expression levels of the above genes were increased after the MPZL1 overexpression. MPZL1 knockdown suppressed cell proliferation, migration, and invasion, reduced the tumorsphere-formation capacity, and restrained the expression levels of CD44 and CD133. However, MPZL1 overexpression promoted the cell proliferation, migration, and invasion, enhanced the tumorsphere-formation capacity, and increased the expression levels of CD44 and CD133. Interestingly, LF3 treatment partially revised the effect of MPZL1 overexpression. These findings were further corroborated by in vivo experiments. We concluded that MPZL1 could suppress the lung adenocarcinoma cells' proliferation, migration, invasion, and lung cancer stem cells characteristics. The underlying mechanism is involved in the activation of β-catenin/TCF-4 signaling.