Discovery of a First-in-Class Degrader for the Lipid Kinase PIKfyve

The phosphoinositide kinase PIKfyve has emerged as anew potentialtherapeutic target in various cancers. However, limited clinical progresshas been achieved with PIKfyve inhibitors. Here, we report the discoveryof a first-in-class PIKfyve degrader 12d (PIK5-12d) byemploying the proteolysis-targeting chimera approach. PIK5-12d potently degraded PIKfyve protein with a DC50 value of1.48 nM and a D (max) value of 97.7% in prostatecancer VCaP cells. Mechanistic studies revealed that it selectivelyinduced PIKfyve degradation in a VHL- and proteasome-dependent manner.PIKfyve degradation by PIK5-12d caused massive cytoplasmicvacuolization and blocked autophagic flux in multiple prostate cancercell lines. Importantly, PIK5-12d was more effectivein suppressing the growth of prostate cancer cells than the parentinhibitor and exerted prolonged inhibition of downstream signaling.Further, intraperitoneal administration of PIK5-12d exhibitedpotent PIKfyve degradation and suppressed tumor proliferation in vivo.Overall, PIK5-12d is a valuable chemical tool for exploringPIKfyve-based targeted therapy.

Automated summary

Researchers have discovered a first-in-class PIKfyve degrader, PIK5-12d, which can effectively degrade PIKfyve protein and inhibit the growth of prostate cancer cells. It provides a valuable chemical tool for exploring PIKfyve-based targeted therapy.