2. Academic Validation
  3. Rational discovery of therapeutic PAK1 allosteric activators

Rational discovery of therapeutic PAK1 allosteric activators

  • Cell. 2026 May 28;189(11):3444-3464.e28. doi: 10.1016/j.cell.2026.03.008.
Yu He 1,  James S H Bae 2,  Elżbieta Nowak 3,  Carlos Outeiral 4,  Daniel A Nissley 4,  Anthony Tumber 5,  Georgina Berridge 6,  Eidarus Salah 5,  Yi Wang 7,  Wenqi He 8,  Hongyuan Zhang 8,  Tangting Chen 9,  Samuel Tusk 10,  Sebastian Mathea 11,  Ying-Jie Wang 12,  Alexander Grassam-Rowe 1,  Philipp Kukura 10,  Christopher J Schofield 5,  Darragh P O'Brien 6,  Andrea Pierangelini 6,  Grant C Churchill 1,  Thomas Lanyon-Hogg 1,  Yunbo Ke 13,  Chao Xu 14,  Tao Ye 15,  Hugh Watkins 12,  Liming Ying 16,  Andreas Koschinski 17,  R John Solaro 18,  Xiaoqiu Tan 9,  Jani R Bolla 7,  Xin Wang 8,  Stefan Knapp 11,  Charlotte M Deane 4,  Manuela Zaccolo 17,  Marcin Nowotny 19,  Ming Lei 20
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
  • 2 Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. Electronic address: [email protected].
  • 3 Laboratory of Protein Structure, International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw, Poland; Preclinical Drug Development Facility at IN-MOL-CELL, International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw, Poland.
  • 4 Department of Statistics, University of Oxford, Oxford OX1 3PB, UK.
  • 5 Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
  • 6 Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK.
  • 7 Department of Biology, University of Oxford, Mansfield Road, Oxford OX1 3SZ, UK.
  • 8 Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
  • 9 Key Laboratory of Medical Electrophysiology of the Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, Sichuan, China.
  • 10 Physical and Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford, South Parks Road, Oxford OX1 3QZ, UK; The Kavli Institute for Nanoscience Discovery, Oxford OX1 3QU, UK.
  • 11 Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany; Structural Genomics Consortium (SGC) and Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Str. 15, 60438 Frankfurt, Germany.
  • 12 Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  • 13 Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.
  • 14 State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
  • 15 State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China; Global AI Drug Discovery Center, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Woman's University, Seoul 03760, Republic of Korea.
  • 16 National Heart and Lung Institute, Imperial College London, Molecular Sciences Research Hub, 82 Wood Lane, London W12 0BZ, UK.
  • 17 Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
  • 18 Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA.
  • 19 Laboratory of Protein Structure, International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw, Poland.
  • 20 Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. Electronic address: [email protected].
PMID: 41923641 DOI: 10.1016/j.cell.2026.03.008
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.

Keywords

HCM; PAK1; autoinhibitory regulation; drug discovery; hypertrophic cardiomyopathy; kinase allosteric activator; p21-activated kinase-1; protein kinase.

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