6‐morpholino‐1,3,5‐triazine derivatives target CapZβ to inhibit endosomal trafficking and metastasis

Abstract

Metastasis is the fundamental cause of cancer mortality, but there are still very few anti-metastatic drugs available. Endosomal trafficking has been implicated in tumor metastasis, and we have recently identified several 6-morpholino-1,3,5-triazine derivatives, including vacuolin-1 (V1), as being inhibitors of this process. Here, we assessed the anti-metastatic activity of V1both in vitro and in vivo. V1 significantly inhibits colony formation, migration, and invasion of various cancer cells in vitro. It also compromises the assembly-disassembly dynamics of focal adhesions (FAs) by inhibiting the recycling and degradation of integrins. In various experimental or transgenic mouse models, V1 significantly suppresses the metastasis and/or tumor growth of breast cancer or melanoma. We further identified capping protein Zβ (CapZβ) as a V1 binding protein, and showed that it is required for the V1-mediated inhibition of migration and metastasis of cancer cells. Collectively, our results indicate that 6-morpholino-1,3,5-triazine derivatives target CapZβ to inhibit endosomal trafficking and metastasis, and suggest that CapZβ is a potential therapeutic target against metastasis.