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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Structural Transformation of a BRAF Inhibitor into a Selective PKR Inhibitor.

Jay Yin1,2, Smriti Srivastava3, Xiaojing Tang1

  • 1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada.

Journal of Medicinal Chemistry
|June 22, 2026
PubMed
Summary
This summary is machine-generated.

Researchers repurposed a cancer drug to create a selective inhibitor for RNA-dependent protein kinase (PKR). This new compound, OICR-403184, shows promise for treating cognitive decline and Alzheimer's disease.

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Area of Science:

  • Biochemistry
  • Neuroscience
  • Drug Discovery

Background:

  • RNA-dependent protein kinase (PKR) is crucial for antiviral responses and memory formation.
  • PKR inhibition shows potential for enhancing memory and reversing cognitive decline in aging and Alzheimer's models.
  • Existing PKR inhibitors lack selectivity and favorable pharmacokinetic profiles, hindering therapeutic applications.

Purpose of the Study:

  • To develop a selective inhibitor of PKR by modifying an existing drug.
  • To identify a novel compound with improved selectivity and therapeutic potential for cognitive disorders.

Main Methods:

  • Screening identified dabrafenib, a BRAF inhibitor, as a PKR lead.
  • X-ray cocrystal structures guided modifications to enhance PKR selectivity.
  • Optimized compound OICR-403184 was synthesized and characterized for its inhibitory activity.

Main Results:

  • Dabrafenib was successfully transformed into a selective PKR inhibitor, OICR-403184.
  • OICR-403184 exhibits significantly reduced BRAF activity (IC50 > 10,000 nM) compared to potent PKR inhibition (IC50 = 263 nM).
  • The compound demonstrated minimal activity against related eIF2α kinases, indicating high selectivity.

Conclusions:

  • OICR-403184 represents a highly selective PKR inhibitor derived from a repurposed BRAF inhibitor.
  • This optimized compound serves as a promising starting point for developing therapeutics targeting PKR for cognitive enhancement and neurodegenerative diseases.