Methuosis
is a form of nonapoptotic cell death characterized by
the accumulation of macropinosome-derived vacuoles. Herein, we identify
PIKFYVE, a class III phosphoinositide (PI) kinase, as the protein
target responsible for the methuosis-inducing activity of indolyl-pyridinyl-propenones
(3-(5-methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one).
We further characterize the effects of chemical substitutions at the
2- and 5-indolyl positions on cytoplasmic vacuolization and PIKFYVE
binding and inhibitory activity. Our study provides a better understanding
of the mechanism of methuosis-inducing indolyl-pyridinyl-propenones.
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