Identification of hPIF1 helicase inhibitors by virtual screening of a Fsp3-enriched library

The PIF1 DNA helicase has functions in genome stability and there is strong evidence for a relation between elevated human PIF1 expression and poor outcomes in cancer patients. Here, we report the discovery, via sequential structure-based virtual screening, of a novel series of compounds that inhibit human PIF1 helicase activity. One active scaffold was identified and confirmed in vitro. Molecular modelling-based design and chemical synthesis ultimately led to the 2,6-diaminopyridine derivative 48 inhibiting hPIF1 with an IC₅₀ of 320 μM. Our results indicate that the new scaffold of 48 selected from virtual screening exhibits potential as a starting point for novel hPIF1 inhibitors.