PIKfyve inhibition in MM disrupts autophagy and lysosome function, increasing MHC expression and cholesterol metabolism.

ABSTRACT:

Abstract

We previously reported a chemogenomics screen that unexpectedly identified phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) as a vulnerable target in multiple myeloma (MM). PIKfyve is an essential regulator of lysosomal function and autophagy. Given the high basal requirement for autophagy in MM for sustainable immunoglobulin synthesis, targeting autophagy holds clinical potential as a novel therapeutic avenue. Here, we report the development and characterization of PIK001 and analogs, potent and selective novel small-molecule inhibitors of PIKfyve. PIK001 demonstrated potent anti-MM activity in vitro, as well as synergistic activity with established anti-MM agents (including venetoclax and selinexor), while retaining efficacy in lenalidomide-resistant models. Multiomic

SUBMITTER: Bonolo de Campos C 

PROVIDER: S-EPMC12883861 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature