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The tetracycline repressor (tetR)‐regulated system is a widely used tool to specifically control gene expression in mammalian cells. Based on this system, we generated a human osteosarcoma cell line, which allows for the inducible expression of an EGFP fusion of the TAR DNA‐binding protein 43 (TDP‐43), which has been linked to neurodegenerative diseases. Consistent with previous findings, TDP‐43 overexpression led to the accumulation of aggregates and limited the viability of U2OS. Using this inducible system, we conducted a chemical screen with a library that included FDA‐approved drugs. While the primary screen identified several compounds that prevented TDP‐43 toxicity, further experiments revealed that these chemicals abrogated the doxycycline‐dependent TDP‐43 expression. This antagonistic effect was observed with both doxycycline and tetracycline, and in several Tet‐On cell lines …