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.