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

[Image: see text] 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 12d (PIK5-12d) by employing the proteolysis-targeting chimera approach.

PIK5-12d potently degraded PIKfyve protein with a DC(50) value of 1.48 nM and a D(max) 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 PIK5-12d caused massive cytoplasmic vacuolization and blocked autophagic flux in multiple prostate cancer cell lines.

Importantly, PIK5-12d 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 PIK5-12d exhibited potent PIKfyve degradation and suppressed tumor proliferation in vivo.

Overall, PIK5-12d is a valuable chemical tool for exploring PIKfyve-based targeted therapy.