Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma

Sophia Gayle, Sean Landrette, Neil Beeharry, Chris Conrad, Marylens Hernandez, Paul Beckett, Shawn M. Ferguson, Talya Mandelkern, Meiling Zheng, Tian Xu, Jonathan Rothberg and Henri Lichenstein

Key Points

  • Apilimod has broad anticancer activity in vitro and in vivo across all subtypes of B-NHL.

  • Apilimod induces B-NHL cytotoxicity through a unique mechanism of action that involves the disruption of lysosomal function.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.


We identified apilimod as an antiproliferative compound by high-throughput screening of clinical-stage drugs. Apilimod exhibits exquisite specificity for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) lipid kinase and has selective cytotoxic activity in B-cell non-Hodgkin lymphoma (B-NHL) compared with normal cells. Apilimod displays nanomolar activity in vitro, and in vivo studies demonstrate single-agent efficacy as well as synergy with approved B-NHL drugs. Using biochemical and knockdown approaches, and discovery of a kinase domain mutation conferring resistance, we demonstrate that apilimod-mediated cytotoxicity is driven by PIKfyve inhibition. Furthermore, a critical role for lysosome dysfunction as a major factor contributing to apilimod’s cytotoxicity is supported by a genome-wide CRISPR screen. In the screen, TFEB (master transcriptional regulator of lysosomal biogenesis) and endosomal/lysosomal genes CLCN7, OSTM1, and SNX10 were identified as important determinants of apilimod sensitivity. These findings thus suggest that disruption of lysosomal homeostasis with apilimod represents a novel approach to treat B-NHL.

  • Submitted September 1, 2016.
  • Accepted January 12, 2017.
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