Related Experiment Video

Updated: Aug 15, 2026

A G-quadruplex DNA-affinity Approach for Purification of Enzymatically Active G4 Resolvase1
11:25

A G-quadruplex DNA-affinity Approach for Purification of Enzymatically Active G4 Resolvase1

Published on: March 18, 2017

Fragment-Based Discovery of Potent RNA-Competitive Inhibitors of the DEAH-Box RNA Helicase DHX8

Benjamin J Read1, Caroline Ewens1, Federica Gigante1

  • 1Centre for Cancer Drug Discovery, Division of Cancer Therapeutics, The Institute of Cancer Research, LondonSM2 5GP, U.K.

Journal of Medicinal Chemistry
|August 13, 2026
PubMed

Insights

Researchers discovered new DHX8 inhibitors targeting cancer. These novel compounds show nanomolar potency and cellular activity, offering a promising therapeutic strategy for oncology by blocking RNA helicase function.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Structural Biology

Background:

  • Human DHX8 is a spliceosomal RNA helicase critical for mRNA release and splicing fidelity.
  • DHX8 is a potential oncology target due to its role in stress-adaptive gene expression and oncogenic stress responses.

Purpose of the Study:

  • To discover and optimize novel RNA-competitive inhibitors of DHX8.
  • To elucidate the structure-activity relationships for DHX8 inhibition.

Main Methods:

  • Structure-guided design based on biophysical fragment screening.
  • Biochemical assays to determine inhibitor potency (nanomolar range).
  • Cellular target engagement assays and in vitro pharmacokinetic studies.

Main Results:

  • Identification of a novel 2-(phenethylthio)nicotinic acid scaffold for DHX8 inhibition.
  • Compound 53 demonstrated nanomolar biochemical potency and cellular activity.
  • Optimization involved targeting specific binding interactions within DHX8, including the Winged-Helix domain.

Conclusions:

  • Novel DHX8 inhibitors were developed with potential as cancer therapeutics.
  • Inhibitor binding to the Winged-Helix domain stabilizes an inactive conformation, blocking RNA translocation.
  • These findings provide a foundation for further development of DHX8-targeted cancer therapies.

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