Demonstrating Ligandability of the LC3A and LC3B Adapter Interface

Autophagy is the common name for
a number of lysosome-based degradation
pathways of cytosolic cargos. The key components of autophagy are
members of Atg8 family proteins involved in almost all steps of the
process, from autophagosome formation to their selective fusion with
lysosomes. In this study, we show that the homologous members of the
human Atg8 family proteins, LC3A and LC3B, are druggable by a small
molecule inhibitor novobiocin. Structure–activity relationship
(SAR) studies of the 4-hydroxy coumarin core scaffold were performed,
supported by a crystal structure of the LC3A dihydronovobiocin complex.
The study reports the first nonpeptide inhibitors for these protein
interaction targets and will lay the foundation for the development
of more potent chemical probes for the Atg8 protein family which may
also find applications for the development of autophagy-mediated degraders
(AUTACs).