化学
前列腺癌
细胞生物学
激酶
癌细胞
癌症研究
癌症
生物化学
生物
遗传学
作者
Chungen Li,Qiao Ye,Xia Jiang,Lianchao Liu,Yang Zheng,Yu Qiu,Caleb Cheng,Fengtao Zhou,Yang Zhou,Weixue Huang,Xiaomei Ren,Yuzhuo Wang,Zhen Wang,Arul M. Chinnaiyan,Ke Ding
标识
DOI:10.1021/acs.jmedchem.3c00912
摘要
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.
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