Patulin and LL‐Z1640‐2 induce apoptosis of cancer cells by decreasing endogenous protein levels of Zic family member 5

Zic family member 5 (ZIC5) is a transcription factor that promotes the survival of several cancer cell types. As ZIC5 is expressed at minimal levels in normal human adult tissues, it is a potential therapeutic target. In this study, we screened a chemical library containing 3398 compounds that includes pre‐existing drugs and compounds with known effects to identify ZIC5 inhibitors. In the first screening, 18 hit compounds decreased GFP intensity in melanoma A375 cells overexpressing GFP‐tagged ZIC5. In the second screening, five compounds that attenuated ZIC5 protein levels in A375 cells were identified. Among them, LL‐Z1640‐2 and patulin selectively induced apoptosis in melanoma cells expressing ZIC5, while only inducing very low levels of apoptosis in normal human melanocytes, which have no detectable ZIC5 expression. LL‐Z1640‐2 and patulin also induced apoptosis in BRAF inhibitor‐resistant melanoma, pancreatic cancer, cholangiocarcinoma and colorectal cancer cells. LL‐Z1640‐2‐ and patulin‐mediated suppression of melanoma proliferation were rescued by ZIC5 overexpression. These results suggest that LL‐Z1640‐2 and patulin are promising compounds that decrease ZIC5 expression to induce apoptosis in cancer cells.