Figure 1. Schematic model of UNI418 mechanism (IMAGE)
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UNI418 inhibits PIKfyve and PIP5K1C, leading to a reduction in intracellular IP6 levels. Under normal conditions, IP6 suppresses the activity of the Cul4A ubiquitin ligase complex, allowing key DNA repair proteins to remain stable. Upon UNI418 treatment, decreased IP6 relieves this suppression, resulting in activation of Cul4A. Activated Cul4A, in association with WDR5, promotes ubiquitination and degradation of homologous recombination proteins such as RAD51 and CHK1. Consequently, DNA repair is impaired, increasing the sensitivity of cancer cells to PARP inhibitors.
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Institute for Basic Science
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