Abstact

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 (IC(50) > 10,000 nM against BRAF vs IC(50) = 263 nM against PKR in vitro), and minimal activity against related eIF2alpha kinases in cells. These findings establish OICR-403184 as a promising chemical starting point for further PKR inhibitor optimization.