A small-molecule PI3Kα activator for cardioprotection and neuroregeneration

TY - JOUR

T1 - A small-molecule PI3Kα activator for cardioprotection and neuroregeneration

AU - Gong, Grace Q.

AU - Bilanges, Benoit

AU - Allsop, Ben

AU - Masson, Glenn R.

AU - Roberton, Victoria

AU - Askwith, Trevor

AU - Oxenford, Sally

AU - Madsen, Ralitsa R.

AU - Conduit, Sarah E.

AU - Bellini, Dom

AU - Fitzek, Martina

AU - Collier, Matt

AU - Najam, Osman

AU - He, Zhenhe

AU - Wahab, Ben

AU - McLaughlin, Stephen H.

AU - Chan, A. W. Edith

AU - Feierberg, Isabella

AU - Madin, Andrew

AU - Morelli, Daniele

AU - Bhamra, Amandeep

AU - Vinciauskaite, Vanesa

AU - Anderson, Karen E.

AU - Surinova, Silvia

AU - Pinotsis, Nikos

AU - Lopez-Guadamillas, Elena

AU - Wilcox, Matthew

AU - Hooper, Alice

AU - Patel, Chandni

AU - Whitehead, Maria A.

AU - Bunney, Tom D.

AU - Stephens, Len R.

AU - Hawkins, Phillip T.

AU - Katan, Matilda

AU - Yellon, Derek M.

AU - Davidson, Sean M.

AU - Smith, David M.

AU - Phillips, James B.

AU - Angell, Richard

AU - Williams, Roger L.

AU - Vanhaesebroeck, Bart

N1 - Copyright: © 2023. The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2023/6/1

Y1 - 2023/6/1

N2 - 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.

AB - 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.

KW - Cell signalling

KW - Drug discovery

KW - Kinases

KW - X-ray crystallography

UR - https://www.scopus.com/pages/publications/85160229754

U2 - 10.1038/s41586-023-05972-2

DO - 10.1038/s41586-023-05972-2

M3 - Article

C2 - 37225977

SN - 0028-0836

VL - 618

SP - 159

EP - 168

JO - Nature

JF - Nature

ER -