Rational discovery of therapeutic PAK1 allosteric activators
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Although kinase activators hold significant therapeutic promise, their development remains challenging and rarely achieved. Here, we report the discovery of direct small-molecule activators of p21-activated kinase-1 (PAK1), a key regulator of cardiac homeostasis, using a rational peptide-guided strategy. Targeting PAK1 autoinhibitory regulation, we identified a previously unrecognized autoinhibition-release site between the autoregulatory region and the kinase domain. Subsequent high-throughput screening and medicinal chemistry optimization yielded selective allosteric activators that enhance PAK1 activity with micromolar potency and isoform selectivity. Structural and mechanistic analyses indicate that these activators disrupt autoinhibitory regulation and promote local and global conformational transitions to the active state. Enhanced PAK1 signaling was confirmed in cardiac cells, and in vivo studies demonstrated therapeutic efficacy in both inherited and acquired cardiac hypertrophy. Collectively, these findings establish rational modulation of kinase autoinhibitory regulation as a potential strategy for the broader discovery of kinase activators, a largely unexplored area of therapeutic development.
Date Issued
2026-05-28
Date Acceptance
2026-03-06
Citation
Cell, 2026, 189 (11), pp.3444-3464.e28
ISSN
0092-8674
Publisher
Elsevier BV
Start Page
3444
End Page
3464.e28
Journal / Book Title
Cell
Volume
189
Issue
11
Copyright Statement
© 2026 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
10.1016/j.cell.2026.03.008
Publication Status
Published
Date Publish Online
2026-03-31