Discovery of Potent and Selective Phosphatidylinositol 3-Phosphate 5-Kinase (PIKfyve) Inhibitors as Methuosis Inducers

  • J Med Chem. 2024 Jan 11;67(1):165-179. doi: 10.1021/acs.jmedchem.3c01039.
Yong Chen  1 ,  Shuai Liu  2 ,  Yuhan Wei  2 ,  Haoche Wei  2 ,  Xue Yuan  2 ,  Baojian Xiong  2 ,  Minghai Tang  2 ,  Tao Yang  2 ,  Zhuang Yang  2 ,  Haoyu Ye  2 ,  Jianhong Yang  2 ,  Lijuan Chen  2  3
Affiliations
  • 1. Innovation Center of Nursing Research and Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China.
  • 2. Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China.
  • 3. Chengdu Zenitar Biomedical Technology Co., Ltd., Chengdu 610041, China.
PMID: 38117948 DOI: 10.1021/acs.jmedchem.3c01039
Abstract

Cytoplasmic vacuolation-associated cell death, known as methuosis, offers a promising nonapoptotic approach for Cancer treatment. In this study, we outline the synthesis and evaluation of potent methuosis-inducing compounds. These compounds selectively induce cell death, characterized by extensive cytoplasmic vacuolation in HeLa and MDA-MB-231 cells. Notably, compound L22 exhibited a remarkable interaction with PIKfyve kinase, boasting a Kd value of 0.47 nM, surpassing the positive controls D-13 and MOMIPP in potency. Furthermore, it is important to highlight that cell death induced by compound L22 is unequivocally attributed to methuosis as it differs from Apoptosis, necrosis, or Autophagy. Importantly, when administered orally, L22 effectively inhibited tumor growth in a HeLa xenograft model without any apparent signs of toxicity. These results underscore the potential of L22 as a valuable tool for in-depth investigations into the mechanisms of methuosis and as a promising lead compound to guide structural optimization.

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