@article{ecb2d398f5df47cc8fd6537759cc5e07,
title = "A small-molecule PI3Kα activator for cardioprotection and neuroregeneration",
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.",
keywords = "Cell signalling, Drug discovery, Kinases, X-ray crystallography",
author = "Gong, {Grace Q.} and Benoit Bilanges and Ben Allsop and Masson, {Glenn R.} and Victoria Roberton and Trevor Askwith and Sally Oxenford and Madsen, {Ralitsa R.} and Conduit, {Sarah E.} and Dom Bellini and Martina Fitzek and Matt Collier and Osman Najam and Zhenhe He and Ben Wahab and McLaughlin, {Stephen H.} and Chan, {A. W. Edith} and Isabella Feierberg and Andrew Madin and Daniele Morelli and Amandeep Bhamra and Vanesa Vinciauskaite and Anderson, {Karen E.} and Silvia Surinova and Nikos Pinotsis and Elena Lopez-Guadamillas and Matthew Wilcox and Alice Hooper and Chandni Patel and Whitehead, {Maria A.} and Bunney, {Tom D.} and Stephens, {Len R.} and Hawkins, {Phillip T.} and Matilda Katan and Yellon, {Derek M.} and Davidson, {Sean M.} and Smith, {David M.} and Phillips, {James B.} and Richard Angell and Williams, {Roger L.} and Bart Vanhaesebroeck",
note = "Funding Information: This research was funded in part by the Wellcome Trust and UKRI (BBRSRC and MRC). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Grant funding details are as follows: UK NIHR UCLH Biomedical Research Centre (to B.V. (High Impact Experimental Medicine Initiative BRC80a/HI/TE/5995 and BRC80b/HI/TE/5995), to B.V. and R.A. (BRC504/CV/BV/101320, BRC732/JK/101400 and RCF309/BVH/101440/2017) and to the UCL Drug Discovery Group (BRC247/HI/DM/101440 and BRC454/HI/JK/104360)); MRC (to R.L.W. (MC_U105184308); to B.V. and R.A. (UCL Proximity to Discovery Fund (MC_PC_15063, MC_PC_16087 and MC_PC_17202); MRC Confidence in Concept (MC_PC_16063 and MC_PC_18063); to G.R.M. and V.V. (MRC iCase Studentship (MR/R01579/1)); to G.R.M. and R.L.W. (Blue Sky collaboration MRC Laboratory of Molecular Biology and AstraZeneca (BSF33)); the Rosetrees Trust (to V.R. (Rosetrees Trust Seedcorn 2020 (100049)) and J.B.P. (UCL Rosetrees Stoneygate Prize 2018; M827)); Cancer Research UK (to B.V. (C23338/A29269 and C23338/A25722)); the BBSRC (to R.A. and B.V. (BBSRC Global Challenges Research Fund Impact Acceleration Account GCRF-IAA), to G.R.M. (BBSRC Capital Equipment Grant BB/V019635/1), and to L.R.S., P.T.H. and K.E.A. (BBSRC Institute Strategic Programme Grant BB/PO13384/1)); the British Heart Foundation (to S.M.D., D.M.Y., B.V. and R.A. (PG/18/44/33790)); the Fidelity Foundation (to T.D.B. and M.K. (180348)) and the UCL Enterprise HEIF Knowledge Exchange and Innovation Fund (to R.A. (KEI2017-05-18)). The UCL Drug Discovery Group received additional support from the Wellcome Trust (Institutional Strategic Support Fund; awarded to UCL (105604/Z/14/Z and 204841/Z/16/Z), with subaward to the Drug Discovery Group (ISSF2/H17RCO/033 and ISSF3/H17RCO/006)). A.B. is supported by a CRUK Cancer Immunotherapy Network Accelerator (CITA) Award (C33499/A20265) and a CRUK UCL Centre award (C416/A25145). S.S. and the UCL Cancer Institute Translational Technology Platforms are supported by a CRUK UCL Centre Award (C416/A25145). Personal fellowships were from EU Marie Sk{\l}odowska-Curie (to G.Q.G. (contract number 839032) and S.E.C. (contract number 838559)) and the Wellcome Trust (to R.R.M. (220464/Z/20/Z)). G.R.M. was supported by the AstraZeneca/LMB Blue Sky Initiative (MC-A024-5PF9G to R.L.W.) and a Henslow Research Fellowship from The Cambridge Philosophical Society and St Catharine{\textquoteright}s College, Cambridge, UK. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission Copyright: {\textcopyright} 2023. The Author(s), under exclusive licence to Springer Nature Limited. ",
year = "2023",
month = jun,
day = "1",
doi = "10.1038/s41586-023-05972-2",
language = "English",
volume = "618",
pages = "159--168",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Research",
}