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

Abstract

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 DC50 value of 1.48 nM and a Dmax 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.

• Authors: Chungen Li, Yuanyuan Qiao, Xia Jiang, Lianchao Liu, Yang Zheng, Yudi Qiu, Caleb Cheng, Fengtao Zhou, Yang Zhou, Weixue Huang, Xiaomei Ren, Yuzhuo Wang, Zhen Wang, Arul M Chinnaiyan, Ke Ding
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 66 Issue 17 Pg. 12432-12445 (09 14 2023) ISSN: 1520-4804 [Electronic] United States
• PMID: 37605297 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Lipids
• PIKFYVE protein, human

Topics

• Humans
• Male
• Autophagy
• Cell Line
• Cytoplasm
• Lipids
• Prostatic Neoplasms (drug therapy)