Identification of Potent Caspase‐8 Inhibitors from a Library of Fluorescent Natural Products Screened by an AIEgen‐Based Light‐Up Probe

Fluorescent natural products are a rich source of drugs and chemical probes, but their innate fluorescence can interfere with fluorescence‐based screening assays. Caspase‐8 is a key player in apoptosis, its inhibition having been found to be beneficial for treatment of inflammatory and neurodegenerative diseases. Small‐molecular inhibitors of caspase‐8 remain sparsely reported, however. In this study, we firstly developed a light‐up probe based on an AIEgen and capable of targeting caspase‐8. This fluorescent dye has a Stokes shift of 200 nm, which could allow the innate fluorescence signals of natural products to be avoided. On screening a library of 86 fluorescent natural products, we found for the first time that gossypol showed potent inhibition of caspase‐8 in vitro and in situ. This unique light‐up probe, coupled with colored natural products, could represent an efficient approach to hit discovery for druggable targets. High‐throughput screening of a library of fluorescent natural products with the aid of an AIEgen‐based light‐up probe revealed that fluorescent gossypol is a potent inhibitor for caspase‐8. This unique light‐up probe, coupled with colored natural products, could represent an efficient approach to hit discovery for druggable targets.