Small molecule PIKfyve inhibitors as cancer therapeutics: Translational promises and limitations.

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ID: 61991
2019
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Abstract
Through synthesis of two rare phosphoinositides, PtdIns(3,5)P and PtdIns5P, the ubiquitously expressed phosphoinositide kinase PIKfyve is implicated in pleiotropic cellular functions. Small molecules specifically inhibiting PIKfyve activity cause cytoplasmic vacuolation in all dividing cells in culture yet trigger non-apoptotic death through excessive vacuolation only in cancer cells. Intriguingly, cancer cell toxicity appears to be inhibitor-specific suggesting that additional targets beyond PIKfyve are affected. One PIKfyve inhibitor - apilimod - is already in clinical trials for treatment of B-cell malignancies. However, apilimod is inactivated in cultured cells and exhibits unexpectedly low plasma levels in patients treated with maximum oral dosage. Thus, the potential widespread use of PIKfyve inhibitors as cancer therapeutics requires progress on multiple fronts: (i) advances in methods for isolating relevant cancer cells from individual patients; (ii) delineation of the molecular mechanisms potentiating the vacuolation induced by PIKfyve inhibitors in sensitive cancer cells; (iii) design of PIKfyve inhibitors with favorable pharmacokinetics; and (iv) development of effective drug combinations.
Reference Key
ikonomov2019smalltoxicology Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Ikonomov, Ognian C;Sbrissa, Diego;Shisheva, Assia;
Journal toxicology and applied pharmacology
Year 2019
DOI
S0041-008X(19)30379-5
URL
Keywords
Cancer cell death pikfyve inhibitors vacuolation

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