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Apilimod, a candidate anticancer therapeutic, arrests not only PtdIns(3,5)P2 but also PtdIns5P synthesis by PIKfyve and induces bafilomycin A1-reversible aberrant endomembrane dilation

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Journal Article - Open Access

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Wayne State University School of Medicine Detroit United States

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We demonstrate that the partially-characterized PIKfyve inhibitor apilimod in addition to blocking the synthesis of PtdIns3,5P2 also blocks the synthesis of PtdIns5P in vitro and in vivo. We further show that the apilimod-induced large translucent cytoplasmic vacuoles, which are typical for PIKfyve inhibition, could be rescued or completely prevented by bafilomycin A1 treatment. Bafilomycin A1 does not affect the reduced by apilimod PtdIns3,5P2 or PtdIns5P but markedly attenuates the elevation of the PIKfyve substrate PtdIns3P, which is accompanied by profoundly decreased endosomal recruitment of fusogenic EEA1. Together, our data demonstrate that apilimod inhibits not only PtdIns3,5P2 but also PtdIns5P synthesis and that the cytoplasmic vacuolization triggered by the inhibitor is precluded or reversed by bafilomycin A1 through a mechanism associated, in part, with reduction in both PtdIns3P levels and EEA1 recruitment.

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  • Medicine and Medical Research
  • Pharmacology

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