A small-molecule PI3Kα activator for cardioprotection and neuroregeneration

Gong, Grace Q.; Bilanges, Benoit; Allsop, Ben; Masson, Glenn R.; Roberton, Victoria; Askwith, Trevor; Oxenford, Sally; Madsen, Ralitsa R.; Conduit, Sarah E.; Bellini, Dom; Fitzek, Martina; Collier, Matt; Najam, Osman; He, Zhenhe; Wahab, Ben; McLaughlin, Stephen H.; Chan, A. W. Edith; Feierberg, Isabella; Madin, Andrew; Morelli, Daniele; Bhamra, Amandeep; Vinciauskaite, Vanesa; Anderson, Karen E.; Surinova, Silvia; Pinotsis, Nikos; Lopez-Guadamillas, Elena; Wilcox, Matthew; Hooper, Alice; Patel, Chandni; Whitehead, Maria A.; Bunney, Tom D.; Stephens, Len R.; Hawkins, Phillip T.; Katan, Matilda; Yellon, Derek M.; Davidson, Sean M.; Smith, David M.; Phillips, James B.; Angell, Richard; Williams, Roger L.; Vanhaesebroeck, Bart

A small-molecule PI3Kα activator for cardioprotection and neuroregeneration

Grace Q. Gong, Benoit Bilanges, Ben Allsop, Glenn R. Masson, Victoria Roberton, Trevor Askwith, Sally Oxenford, Ralitsa R. Madsen, Sarah E. Conduit, Dom Bellini, Martina Fitzek, Matt Collier, Osman Najam, Zhenhe He, Ben Wahab, Stephen H. McLaughlin, A. W. Edith Chan, Isabella Feierberg, Andrew Madin, Daniele Morelli, Amandeep Bhamra, Vanesa Vinciauskaite, Karen E. Anderson, Silvia Surinova, Nikos Pinotsis, Elena Lopez-Guadamillas, Matthew Wilcox, Alice Hooper, Chandni Patel, Maria A. Whitehead, Tom D. Bunney, Len R. Stephens, Phillip T. Hawkins, Matilda Katan, Derek M. Yellon, Sean M. Davidson, David M. Smith, James B. Phillips, Richard Angell, Roger L. Williams and Bart Vanhaesebroeck ()
Additional contact information
Grace Q. Gong: University College London
Benoit Bilanges: University College London
Ben Allsop: University College London
Glenn R. Masson: Medical Research Council Laboratory of Molecular Biology
Victoria Roberton: University College London
Trevor Askwith: University College London
Sally Oxenford: University College London
Ralitsa R. Madsen: University College London
Sarah E. Conduit: University College London
Dom Bellini: Medical Research Council Laboratory of Molecular Biology
Martina Fitzek: AstraZeneca, Alderley Park
Matt Collier: AstraZeneca, Alderley Park
Osman Najam: University College London
Zhenhe He: University College London
Ben Wahab: Cardiff University
Stephen H. McLaughlin: Medical Research Council Laboratory of Molecular Biology
A. W. Edith Chan: University College London
Isabella Feierberg: AstraZeneca
Andrew Madin: AstraZeneca
Daniele Morelli: University College London
Amandeep Bhamra: University College London
Vanesa Vinciauskaite: University of Dundee
Karen E. Anderson: Babraham Institute
Silvia Surinova: University College London
Nikos Pinotsis: Birkbeck College
Elena Lopez-Guadamillas: University College London
Matthew Wilcox: University College London
Alice Hooper: University College London
Chandni Patel: University College London
Maria A. Whitehead: University College London
Tom D. Bunney: University College London
Len R. Stephens: Babraham Institute
Phillip T. Hawkins: Babraham Institute
Matilda Katan: University College London
Derek M. Yellon: University College London
Sean M. Davidson: University College London
David M. Smith: AstraZeneca
James B. Phillips: University College London
Richard Angell: University College London
Roger L. Williams: Medical Research Council Laboratory of Molecular Biology
Bart Vanhaesebroeck: University College London

Nature, 2023, vol. 618, issue 7963, 159-168

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-05972-2

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