2. Academic Validation
  3. A small-molecule PI3Kα activator for cardioprotection and neuroregeneration

A small-molecule PI3Kα activator for cardioprotection and neuroregeneration

  • Nature. 2023 Jun;618(7963):159-168. doi: 10.1038/s41586-023-05972-2.
Grace Q Gong 1,  Benoit Bilanges 1,  Ben Allsop 2,  Glenn R Masson 3 4,  Victoria Roberton 5,  Trevor Askwith 2,  Sally Oxenford 2,  Ralitsa R Madsen 1,  Sarah E Conduit 1,  Dom Bellini 3,  Martina Fitzek 6,  Matt Collier 6,  Osman Najam 7,  Zhenhe He 7,  Ben Wahab 8,  Stephen H McLaughlin 3,  A W Edith Chan 9,  Isabella Feierberg 10,  Andrew Madin 11,  Daniele Morelli 1,  Amandeep Bhamra 12,  Vanesa Vinciauskaite 4,  Karen E Anderson 13,  Silvia Surinova 12,  Nikos Pinotsis 14,  Elena Lopez-Guadamillas 1,  Matthew Wilcox 5,  Alice Hooper 2,  Chandni Patel 2,  Maria A Whitehead 1,  Tom D Bunney 15,  Len R Stephens 13,  Phillip T Hawkins 13,  Matilda Katan 15,  Derek M Yellon 7,  Sean M Davidson 7,  David M Smith 16,  James B Phillips 5,  Richard Angell 2 8,  Roger L Williams 3,  Bart Vanhaesebroeck 17
Affiliations

Affiliations

  • 1 Cell Signalling, Cancer Institute, University College London, London, UK.
  • 2 Drug Discovery Group, Translational Research Office, University College London, London, UK.
  • 3 Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
  • 4 Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, UK.
  • 5 UCL Centre for Nerve Engineering, UCL School of Pharmacy, University College London, London, UK.
  • 6 Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Alderley Park, Macclesfield, UK.
  • 7 The Hatter Cardiovascular Institute, University College London, London, UK.
  • 8 Medicines Discovery Institute, School of Biosciences, Cardiff University, Cardiff, UK.
  • 9 Wolfson Institute for Biomedical Research, University College London, London, UK.
  • 10 Molecular AI, Discovery Sciences, R&D, AstraZeneca, Waltham, MA, USA.
  • 11 Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK.
  • 12 Proteomics Research Translational Technology Platform, Cancer Institute, University College London, London, UK.
  • 13 Signalling Programme, Babraham Institute, Cambridge, UK.
  • 14 Institute of Structural and Molecular Biology, Birkbeck College, London, UK.
  • 15 Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London, UK.
  • 16 Emerging Innovations, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK.
  • 17 Cell Signalling, Cancer Institute, University College London, London, UK. [email protected].
PMID: 37225977 DOI: 10.1038/s41586-023-05972-2
Abstract

Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development1-5. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as Cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia-reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development.

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Products
  • Cat. No.
    Product Name
    Description
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  • HY-154848
    99.56%, PI3K Activator