2. Academic Validation
  3. Discovery of a First-in-Class Degrader for the Lipid Kinase PIKfyve

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

  • J Med Chem. 2023 Sep 14;66(17):12432-12445. doi: 10.1021/acs.jmedchem.3c00912.
Chungen Li 1,  Yuanyuan Qiao 2 3,  Xia Jiang 2,  Lianchao Liu 1,  Yang Zheng 2,  Yudi Qiu 1,  Caleb Cheng 2,  Fengtao Zhou 4,  Yang Zhou 4,  Weixue Huang 1,  Xiaomei Ren 1,  Yuzhuo Wang 5,  Zhen Wang 1,  Arul M Chinnaiyan 2 3 6 7,  Ke Ding 1 8 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Roadd, Shanghai 200032, People's Republic of China.
  • 2 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3 Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou 511400, People's Republic of China.
  • 5 The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada.
  • 6 Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 7 Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 8 Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, People's Republic of China.
PMID: 37605297 DOI: 10.1021/acs.jmedchem.3c00912
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.

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