9YUF

PKR kinase domain - Dabrafenib complex

Summary for 9YUF

• Entry DOI: 10.2210/pdb9yuf/pdb
• Descriptor: Interferon-induced, double-stranded RNA-activated protein kinase, Dabrafenib (2 entities in total)
• Functional Keywords: protein kinase, inhibitor, complex, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 132280.33

Authors

Yin, J.Z.,Sicheri, F. (deposition date: 2025-10-22, release date: 2026-07-01)

Primary citation

Yin, J.,Srivastava, S.,Tang, X.,Galbraith, C.,Uchenunu, O.,Miller, J.,Liu, Y.,Crescenzi, I.,Kiyota, T.,Kurinov, I.,Costa-Mattioli, M.,Laufer, R.,Aman, A.,Rottapel, R.,Ramnauth, J.,Haakonsen, D.L.,Uehling, D.E.,Sicheri, F.
Structural Transformation of a BRAF Inhibitor into a Selective PKR Inhibitor.
J.Med.Chem., 2026

PubMed 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 , which shows markedly reduced BRAF activity, improved PKR selectivity (IC > 10,000 nM against BRAF vs IC = 263 nM against PKR ), and minimal activity against related eIF2α kinases in cells. These findings establish as a promising chemical starting point for further PKR inhibitor optimization.

PubMed: 42324916
DOI: 10.1021/acs.jmedchem.5c03664

Experimental method

X-RAY DIFFRACTION (2.5 Å)