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

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.