WDR19 Inhibitors

Chemical inhibitors of WDR19 function predominantly by disrupting microtubule dynamics or the regulatory pathways that control ciliary transport and assembly processes. Ciliobrevin A, for instance, impairs the hedgehog signaling pathway, which is critical for ciliogenesis, by inhibiting dynein. Since dynein motors are essential for the intraflagellar transport system where WDR19 operates, the inhibition of dynein by Ciliobrevin A can subsequently impair WDR19 function. Similarly, Mebendazole and Griseofulvin exert their inhibitory effects by interfering with microtubule polymerization, a process fundamental for the trafficking role of WDR19. Mebendazole destabilizes microtubules while Griseofulvin binds to tubulin, leading to microtubule disassembly. Both actions result in a compromised microtubule framework, thereby impeding WDR19's transport function within cilia.

Other chemical inhibitors, such as Colchicine, Vincristine, Nocodazole, Podophyllotoxin, and Thiabendazole, also target microtubule dynamics but through different mechanisms. Colchicine binds to tubulin, inhibiting its polymerization and the formation of microtubules, on which WDR19 relies for ciliary cargo transport. Vincristine and Podophyllotoxin are microtubule-destabilizing agents that inhibit the assembly of microtubules, while Nocodazole interferes directly with microtubule polymerization. Thiabendazole, like Mebendazole and Griseofulvin, disrupts microtubule polymerization, further supporting the inhibition of WDR19's role in ciliary function. Conversely, Paclitaxel stabilizes microtubules, preventing their depolymerization, which paradoxically disrupts the dynamic nature of microtubules required for WDR19's function. In addition, Monastrol and Alsterpaullone disrupt processes upstream of microtubule-based transport. Monastrol inhibits the kinesin Eg5, affecting spindle formation and potentially the anterograde transport within cilia where WDR19 is active. Alsterpaullone targets cyclin-dependent kinases, which are integral to the regulation of ciliogenesis and intraflagellar transport, thereby disrupting WDR19's associated activities.