A small-molecule PI3Kα activator for cardioprotection and neuroregeneration.

Autor: Gong GQ; Cell Signalling, Cancer Institute, University College London, London, UK., Bilanges B; Cell Signalling, Cancer Institute, University College London, London, UK., Allsop B; Drug Discovery Group, Translational Research Office, University College London, London, UK., Masson GR; Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.; Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, UK., Roberton V; UCL Centre for Nerve Engineering, UCL School of Pharmacy, University College London, London, UK., Askwith T; Drug Discovery Group, Translational Research Office, University College London, London, UK., Oxenford S; Drug Discovery Group, Translational Research Office, University College London, London, UK., Madsen RR; Cell Signalling, Cancer Institute, University College London, London, UK., Conduit SE; Cell Signalling, Cancer Institute, University College London, London, UK., Bellini D; Medical Research Council Laboratory of Molecular Biology, Cambridge, UK., Fitzek M; Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Alderley Park, Macclesfield, UK., Collier M; Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Alderley Park, Macclesfield, UK., Najam O; The Hatter Cardiovascular Institute, University College London, London, UK., He Z; The Hatter Cardiovascular Institute, University College London, London, UK., Wahab B; Medicines Discovery Institute, School of Biosciences, Cardiff University, Cardiff, UK., McLaughlin SH; Medical Research Council Laboratory of Molecular Biology, Cambridge, UK., Chan AWE; Wolfson Institute for Biomedical Research, University College London, London, UK., Feierberg I; Molecular AI, Discovery Sciences, R&D, AstraZeneca, Waltham, MA, USA., Madin A; Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK., Morelli D; Cell Signalling, Cancer Institute, University College London, London, UK., Bhamra A; Proteomics Research Translational Technology Platform, Cancer Institute, University College London, London, UK., Vinciauskaite V; Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, UK., Anderson KE; Signalling Programme, Babraham Institute, Cambridge, UK., Surinova S; Proteomics Research Translational Technology Platform, Cancer Institute, University College London, London, UK., Pinotsis N; Institute of Structural and Molecular Biology, Birkbeck College, London, UK., Lopez-Guadamillas E; Cell Signalling, Cancer Institute, University College London, London, UK., Wilcox M; UCL Centre for Nerve Engineering, UCL School of Pharmacy, University College London, London, UK., Hooper A; Drug Discovery Group, Translational Research Office, University College London, London, UK., Patel C; Drug Discovery Group, Translational Research Office, University College London, London, UK., Whitehead MA; Cell Signalling, Cancer Institute, University College London, London, UK., Bunney TD; Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London, UK., Stephens LR; Signalling Programme, Babraham Institute, Cambridge, UK., Hawkins PT; Signalling Programme, Babraham Institute, Cambridge, UK., Katan M; Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London, UK., Yellon DM; The Hatter Cardiovascular Institute, University College London, London, UK., Davidson SM; The Hatter Cardiovascular Institute, University College London, London, UK., Smith DM; Emerging Innovations, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK., Phillips JB; UCL Centre for Nerve Engineering, UCL School of Pharmacy, University College London, London, UK., Angell R; Drug Discovery Group, Translational Research Office, University College London, London, UK.; Medicines Discovery Institute, School of Biosciences, Cardiff University, Cardiff, UK., Williams RL; Medical Research Council Laboratory of Molecular Biology, Cambridge, UK., Vanhaesebroeck B; Cell Signalling, Cancer Institute, University College London, London, UK. bart.vanh@ucl.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2023 Jun; Vol. 618 (7963), pp. 159-168. Date of Electronic Publication: 2023 May 24.
DOI: 10.1038/s41586-023-05972-2
Abstrakt: Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development 1-5 . 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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