BibTex format
@article{He:2026:10.1016/j.cell.2026.03.008,
author = {He, Y and Bae, JSH and Nowak, E and Outeiral, C and Nissley, DA and Tumber, A and Berridge, G and Salah, E and Wang, Y and He, W and Zhang, H and Chen, T and Tusk, S and Mathea, S and Wang, Y-J and Grassam-Rowe, A and Kukura, P and Schofield, CJ and OBrien, DP and Pierangelini, A and Churchill, GC and Lanyon-Hogg, T and Ke, Y and Xu, C and Ye, T and Watkins, H and Ying, L and Koschinski, A and Solaro, RJ and Tan, X and Bolla, JR and Wang, X and Knapp, S and Deane, CM and Zaccolo, M and Nowotny, M and Lei, M},
doi = {10.1016/j.cell.2026.03.008},
journal = {Cell},
pages = {3444--3464.e28},
title = {Rational discovery of therapeutic PAK1 allosteric activators},
url = {http://dx.doi.org/10.1016/j.cell.2026.03.008},
volume = {189},
year = {2026}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - 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.
AU - He,Y
AU - Bae,JSH
AU - Nowak,E
AU - Outeiral,C
AU - Nissley,DA
AU - Tumber,A
AU - Berridge,G
AU - Salah,E
AU - Wang,Y
AU - He,W
AU - Zhang,H
AU - Chen,T
AU - Tusk,S
AU - Mathea,S
AU - Wang,Y-J
AU - Grassam-Rowe,A
AU - Kukura,P
AU - Schofield,CJ
AU - OBrien,DP
AU - Pierangelini,A
AU - Churchill,GC
AU - Lanyon-Hogg,T
AU - Ke,Y
AU - Xu,C
AU - Ye,T
AU - Watkins,H
AU - Ying,L
AU - Koschinski,A
AU - Solaro,RJ
AU - Tan,X
AU - Bolla,JR
AU - Wang,X
AU - Knapp,S
AU - Deane,CM
AU - Zaccolo,M
AU - Nowotny,M
AU - Lei,M
DO - 10.1016/j.cell.2026.03.008
EP - 3464
PY - 2026///
SN - 0092-8674
SP - 3444
TI - Rational discovery of therapeutic PAK1 allosteric activators
T2 - Cell
UR - http://dx.doi.org/10.1016/j.cell.2026.03.008
UR - https://doi.org/10.1016/j.cell.2026.03.008
VL - 189
ER -