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

The phosphoinositide kinase PIKfyve has emerged as a new potential therapeutic target in various cancers. However, limited clinical progress has been achieved with PIKfyve inhibitors. Here, we report the discovery of a first-in-class PIKfyve degrader by employing the proteolysis-targeting chimera approach. potently degraded PIKfyve protein with a DC value of 1.48 nM and a value of 97.7% in prostate cancer VCaP cells. Mechanistic studies revealed that it selectively induced PIKfyve degradation in a VHL- and proteasome-dependent manner. PIKfyve degradation by caused massive cytoplasmic vacuolization and blocked autophagic flux in multiple prostate cancer cell lines. Importantly, was more effective in suppressing the growth of prostate cancer cells than the parent inhibitor and exerted prolonged inhibition of downstream signaling. Further, intraperitoneal administration of exhibited potent PIKfyve degradation and suppressed tumor proliferation in vivo. Overall, is a valuable chemical tool for exploring PIKfyve-based targeted therapy.