Aplyronines and mycalolides: marine macrolides with diverse mechanisms for modulating cytoskeletal protein–protein interactions

Abstract This review summarizes recent advances in the synthesis, structure–activity relationships (SAR), and mode of action studies of marine-derived actin-depolymerizing macrolides, particularly aplyronines and mycalolides. Although these compounds have long been recognized as potent actin-targeting cytotoxins, recent chemical biology studies have revealed more complex mechanisms involving modulation of protein–protein interactions (PPIs) within the cytoskeleton. Synthetic efforts have enabled access to structurally diverse analogs, clarifying the distinct roles of the macrolactone and side-chain moieties in actin binding and cytotoxicity. Chemical probe development, including fluorescent, biotinylated, and photoaffinity-tagged derivatives, has facilitated the identification of tubulin as an additional target. Aplyronine A forms a heterotrimeric complex with actin and α/β-tubulin, acting as a molecular glue that destabilizes microtubules (MTs). In contrast, mycalolide C binds to tubulin independently of actin and enhances paclitaxel-induced MT assembly. Molecular modeling studies further support these distinct binding modes, revealing how these macrolides either disrupt or stabilize tubulin interactions. Collectively, these findings highlight the multiple functionalities of actin-binding macrolides as modulators of cytoskeletal PPIs and underscore their potential as lead compounds for the development of novel anticancer agents targeting MT dynamics.