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

  • Bioorg Med Chem Lett. 2025 Jun 21:128:130314. doi: 10.1016/j.bmcl.2025.130314.
Mark J A Wever  1 ,  Francesca R Scommegna  2 ,  Jean-François Poisson  3 ,  Vincent Rodeschini  4 ,  Didier Roche  5 ,  Cyril M Sanders  6
Affiliations
  • 1. Edelris, Bioparc, Bioserra 1 Building, 69008 Lyon, France; Univ. Grenoble Alpes, CNRS, DCM, 38000, Grenoble, France.
  • 2. Division of Clinical Medicine, School of Medicine & Population Health, University of Sheffield, Beech Hill Rd., Sheffield S10 2RX, United Kingdom.
  • 3. Univ. Grenoble Alpes, CNRS, DCM, 38000, Grenoble, France.
  • 4. Edelris, Bioparc, Bioserra 1 Building, 69008 Lyon, France.
  • 5. Edelris, Bioparc, Bioserra 1 Building, 69008 Lyon, France. Electronic address: [email protected].
  • 6. Division of Clinical Medicine, School of Medicine & Population Health, University of Sheffield, Beech Hill Rd., Sheffield S10 2RX, United Kingdom. Electronic address: [email protected].
PMID: 40550429 DOI: 10.1016/j.bmcl.2025.130314
Abstract

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.

Keywords
Cancer; Fsp3-enriched library; Helicase inhibitor; PIF1; Structure-based drug discovery; Virtual screening.
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