Non-Catalytic Inhibitors of the p38/MK2 Interface: Repurposing Approved Drugs to Target Neuroinflammation in Alzheimer’s Disease

Neuroinflammation is a key driver of Alzheimer’s
disease
and an emerging therapeutic target. The p38/MK2 pathway regulates
microglial cytokine production, yet previous attempts have not yielded
modulators with clinically suitable properties. Here, we apply an
integrative structure-guided and screening strategy to identify small-molecule
disruptors of the p38/MK2 protein–protein interaction (PPI).
Virtual screening of FDA-approved drugs prioritized nilotinib, a BCR-ABL
inhibitor, as a putative PPI disruptor. Biochemical and molecular
dynamics analyses confirmed that nilotinib binds to p38, blocks MK2
association, and suppresses cytokine release in microglia. Guided
by these findings, we developed a lysate-based TR-FRET ultrahigh-throughput
assay that identified additional inhibitors, including α1-adrenergic antagonists doxazosin, terazosin, and alfuzosin.
These compounds suppressed cytokine induction via docking groove blockade.
Together, these results establish a non-ATP-competitive approach for
selectively targeting the p38/MK2 complex and highlight the translational
potential of drug repurposing to modulate neuroinflammation in Alzheimer’s
disease.