Rational discovery of therapeutic PAK1 allosteric activators - PubMed
3 hours ago
- #kinase activation
- #cardiac hypertrophy
- #drug discovery
- The text discusses the discovery of small-molecule activators for p21-activated kinase-1 (PAK1), a regulator of cardiac homeostasis.
- A rational peptide-guided strategy was used to target PAK1's autoinhibitory regulation, identifying a new autoinhibition-release site.
- High-throughput screening and medicinal chemistry led to selective allosteric activators with micromolar potency and isoform specificity.
- Structural studies show these activators disrupt autoinhibition and promote conformational changes to an active state.
- Enhanced PAK1 signaling was confirmed in cardiac cells, and in vivo studies showed efficacy in treating cardiac hypertrophy.
- The findings propose modulating kinase autoinhibitory regulation as a strategy for developing kinase activators, an underexplored therapeutic area.