Identification and optimization of first-in-class RNA helicase inhibitors of DDX1, LGP2, and MDA5

  • Eur J Med Chem. 2026 May 5:309:118724. doi: 10.1016/j.ejmech.2026.118724.
Xiaowen Wang  1 ,  Feijun Wang  2 ,  Deyu Kong  2 ,  Dilipkumar Uredi  2 ,  Fengling Li  3 ,  Feng Li  2 ,  Jayachandra Rayadurgam  2 ,  Hanxuan Li  2 ,  Esther Wolf  4 ,  U Hang Chan  5 ,  Irene Chau  3 ,  Hong Zeng  3 ,  Julia Garcia Perez  3 ,  Derek J Wilson  6 ,  Frances M Bashore  7 ,  Xiaodong Wang  2 ,  Levon Halabelian  8 ,  Kevin J Frankowski  2 ,  Dmitri Kireev  9 ,  Alison D Axtman  10
Affiliations
  • 1. Department of Chemistry, University of Missouri, Columbia, MO, 65211, USA.
  • 2. Center for Integrative Chemical Biology and Drug Discovery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 3. Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada.
  • 4. Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada; Department of Chemistry, York University, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
  • 5. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
  • 6. Department of Chemistry, York University, Toronto, ON, Canada.
  • 7. Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
  • 8. Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • 9. Department of Chemistry, University of Missouri, Columbia, MO, 65211, USA. Electronic address: [email protected].
  • 10. Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. Electronic address: [email protected].
PMID: 41795418 DOI: 10.1016/j.ejmech.2026.118724
Abstract

RNA helicases are essential, dynamic proteins that consume ATP to unwind and rearrange RNA. These activities place RNA helicases in roles as central mediators of signaling, especially those pathways dependent on RNA metabolism. Their binding of both ATP and RNA, as well as limited literature examples of small molecule ligands, support the tractability of RNA helicases. We employed structure-based virtual screening to rationally identify ligands that occupy the ATP-binding site of three human DExD/H-box RNA helicases: MDA5, LGP2, and DDX1. Following alignment of the well conserved nucleotide binding pocket for these RNA helicases, we docked and refined the list of potential ligands from the MolPort-2022-03 ligand library of ∼3.7 million members. A chemical lead with favorable solubility emerged from the 144 purchased compounds, which were evaluated in MDA5, LGP2, and DDX1 ATPase assays as well as corresponding SPR assays. It was found to be ATP un-competitive for MDA5 and to have similar affinity for the three RNA helicases. Analogs of the lead compound were designed to optimize the potency and selectivity of the scaffold, yielding both pan-helicase inhibitors and Other analogs that are biased toward MDA5 inhibition.

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