Structural Transformation of a BRAF Inhibitor into a Selective PKR Inhibitor

  • J Med Chem. 2026 Jul 9;69(13):15227-15246. doi: 10.1021/acs.jmedchem.5c03664.
Jay Yin  1  2 ,  Smriti Srivastava  3 ,  Xiaojing Tang  1 ,  Caleb Galbraith  1  4 ,  Oro Uchenunu  5 ,  Joshua Miller  1 ,  Yuwei Liu  6 ,  Isabella Crescenzi  1 ,  Taira Kiyota  3 ,  Igor Kurinov  7 ,  Mauro Costa-Mattioli  6 ,  Radek Laufer  3 ,  Ahmed Aman  3  8 ,  Robert Rottapel  5  9  10 ,  Jailall Ramnauth  3 ,  Diane L Haakonsen  1  4 ,  David E Uehling  3 ,  Frank Sicheri  1  2  4
Affiliations
  • 1. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada.
  • 2. Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  • 3. Drug Discovery Program, Ontario Institute for Cancer Research, MaRS Centre, , Toronto, Ontario M5G 0A3, Canada.
  • 4. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  • 5. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1L7, Canada.
  • 6. Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, United States.
  • 7. NE-CAT APS, Building 436E, Argonne National Laboratory, 9700 S. Cass Avenue, Argonne, Illinois 60439, United States.
  • 8. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
  • 9. Departments of Medicine, Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 10. Division of Rheumatology, St Michael's Hospital, Toronto, Ontario M5B 1W8, Canada.
PMID: 42324916 DOI: 10.1021/acs.jmedchem.5c03664
Abstract

The RNA-dependent protein kinase PKR regulates responses to viral Infection and has emerging roles in memory formation. Inhibition of PKR enhances long-term memory in mice and reverses cognitive decline in models of aging and Alzheimer's disease. However, existing PKR inhibitors have poor selectivity and pharmacokinetic properties, limiting therapeutic development. Here, we describe the transformation of dabrafenib, an FDA-approved oncogenic BRAF inhibitor, into a selective PKR inhibitor. Dabrafenib was identified by screening as a promising PKR lead with similar potency against BRAF and PKR. Guided by X-ray cocrystal structures, we introduced modifications that removed BRAF while retaining PKR inhibition. This optimization yielded OICR-403184, which shows markedly reduced BRAF activity, improved PKR selectivity (IC50 > 10,000 nM against BRAF vs IC50 = 263 nM against PKR in vitro), and minimal activity against related eIF2α kinases in cells. These findings establish OICR-403184 as a promising chemical starting point for further PKR inhibitor optimization.

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