Design, synthesis, and affinity evaluations of PP2A-targeting spiroketal derivatives based on structure-activity relationship studies of marine toxin okadaic acid fragments

Protein phosphatase 2A (PP2A), a member of the phosphoprotein phosphatase (PPP) family, plays a pivotal role in regulating tau dephosphorylation, thereby maintaining the functional integrity of this brain-specific protein in microtubule assembly. Progressive downregulation of PP2A has been implicated in the pathogenesis of Alzheimer’s disease (AD). The identification of high-affinity PP2A ligands presents a promising avenue for monitoring early-stage dementia progression through alternative molecular mechanisms. Utilizing the catalytic binding pocket model of PP1 as a structural surrogate for PPPs, three distinct fragments derived from various natural PP2A inhibitors were found to exhibit equivalent binding functionality. Building upon this framework in small-molecule design, a synthetic spiroketal compound was developed based on the C1–C14 acidic fragment of okadaic acid (OA), a PP2A-selective inhibitor. This compound emerges as a promising candidate for further therapeutic and diagnostic investigation.