Détail du document
Identifiant
oai:pubmedcentral.nih.gov:1051...
Auteur
Li, Chungen Qiao, Yuanyuan Jiang, Xia Liu, Lianchao Zheng, Yang Qiu, Yudi Cheng, Caleb Zhou, Fengtao Zhou, Yang Huang, Weixue Ren, Xiaomei Wang, Yuzhuo Wang, Zhen Chinnaiyan, Arul M. Ding, KeLangue
enEditeur
American Chemical Society
Catégorie
ACS AuthorChoice
Année
2023
Date de référencement
26/09/2023
Mots clés
cancer prostate degradation pik5-12dRésumé
[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.
Li, Chungen,Qiao, Yuanyuan,Jiang, Xia,Liu, Lianchao,Zheng, Yang,Qiu, Yudi,Cheng, Caleb,Zhou, Fengtao,Zhou, Yang,Huang, Weixue,Ren, Xiaomei,Wang, Yuzhuo,Wang, Zhen,Chinnaiyan, Arul M.,Ding, Ke, 2023, Discovery of a First-in-Class Degrader for the Lipid Kinase PIKfyve, American Chemical Society
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