Related Experiment Video

Updated: Sep 12, 2025

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Tetrahydropyrazolopyridinones as a Novel Class of Potent and Highly Selective LIMK Inhibitors

Alex G Baldwin1, David W Foley1, D Heulyn Jones1

  • 1Medicines Discovery Institute, School of Biosciences, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, United Kingdom.

Journal of Medicinal Chemistry
|August 6, 2025
PubMed

Insights

Researchers developed a novel dual LIMK1/2 inhibitor, MDI-117740, offering high selectivity and improved properties for studying diseases linked to LIMK overactivation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Lethal-interactive motif kinase (LIMK) enzymes regulate actin dynamics crucial for cell functions.
  • Overactive LIMK is linked to diseases like cancer and neurodegeneration.
  • Selective LIMK inhibitors are needed to understand disease mechanisms.

Purpose of the Study:

  • Discover novel, potent, and selective dual LIMK1/2 inhibitors.
  • Develop a chemical probe for investigating LIMK roles in health and disease.

Main Methods:

  • Structure-based drug design utilizing a tetrahydropyrazolopyridinone scaffold.
  • Identification and characterization of MDI-117740 (compound 69).
  • Assessment of selectivity and drug-metabolizing and pharmacokinetic (DMPK) properties.

Main Results:

  • MDI-117740 identified as a potent dual LIMK1/2 inhibitor.
  • Compound 69 exhibits significantly improved DMPK properties for in vivo studies.
  • MDI-117740 demonstrates exceptional selectivity, with minimal off-target activity, including RIPK1.

Conclusions:

  • MDI-117740 represents the most selective LIMK inhibitor reported to date.
  • This chemical probe facilitates research into LIMK activation in physiological and pathological contexts.
  • The findings support the development of new therapeutics targeting LIMK-related disorders.

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