牛津大学雷鸣团队近日取得一项新成果。经过不懈努力，他们研究出合理发现治疗性PAK1变构激活剂。该研究于2026年3月31日发表于国际一流学术期刊《细胞》杂志上。
小组报道了p21活化激酶-1 （PAK1）的直接小分子激活剂的发现，PAK1是心脏稳态的关键调节因子，这是一种合理的肽引导策略。针对PAK1的自抑制调控，课题组在自调控区和激酶结构域之间发现了一个以前未被识别的自抑制释放位点。随后的高通量筛选和药物化学优化产生了选择性变构激活剂，以微摩尔效价和异构体选择性增强PAK1活性。
结构和机制分析表明，这些激活剂破坏自抑制调节，促进局部和全局构象过渡到活性状态。在心脏细胞中证实了PAK1信号的增强，并且在体内研究证明了对遗传性和获得性心脏肥厚的治疗效果。总的来说，这些发现建立了激酶自身抑制调节的合理调节作为更广泛发现激酶激活剂的潜在策略，这是一个很大程度上未开发的治疗发展领域。
据了解，虽然激酶激活剂具有重要的治疗前景，但它们的发展仍然具有挑战性，很少实现。
附：英文原文
Title: Rational discovery of therapeutic PAK1 allosteric activators
Author: Yu He, James S.H. Bae, Elbieta Nowak, Carlos Outeiral, Daniel A. Nissley, Anthony Tumber, Georgina Berridge, Eidarus Salah, Yi Wang, Wenqi He, Hongyuan Zhang, Tangting Chen, Samuel Tusk, Sebastian Mathea, Ying-Jie Wang, Alexander Grassam-Rowe, Philipp Kukura, Christopher J. Schofield, Darragh P. O’Brien, Andrea Pierangelini, Grant C. Churchill, Thomas Lanyon-Hogg, Yunbo Ke, Chao Xu, Tao Ye, Hugh Watkins, Liming Ying, Andreas Koschinski, R. John Solaro, Xiaoqiu Tan, Jani R. Bolla, Xin Wang, Stefan Knapp, Charlotte M. Deane, Manuela Zaccolo, Marcin Nowotny, Ming Lei
Issue&Volume: 2026-03-31
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.
DOI: 10.1016/j.cell.2026.03.008
Source: https://www.cell.com/cell/abstract/S0092-8674(26)00275-8