Design of 20-deoxyingenol-esters-based PKC agonists and their lysosome biogenesis-enhancing activity.

ABSTRACT: The activation of conventional (α) and novel (δ) protein kinase C (PKC) isoforms promotes lysosomal biogenesis, a critical process for clearance of pathogenic protein aggregates including β-amyloid (Aβ) and phosphorylated Tau (p-Tau) in neurodegenerative disorders. Notably, PKC activators HEP14/15, characterized by 20-methyl moiety, fail to establish classical C1B domain pharmacophore interactions, suggesting a non-canonical activation mechanism. In this study, structural diversification of 20-deoxyingenol through esterification and acetonide protection yielded 18 new derivatives (2-19). Systematic screening revealed their lysosome-promoting activities, with structure-activity relationship analysis identifying compounds 4 and 18 as superior autophagy inducers. At 20 μM, these derivatives e

SUBMITTER: Wan JJ 

PROVIDER: S-EPMC12151967 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature