@article {36579,
	title = {A small-molecule PI3Kalpha activator for cardioprotection and neuroregeneration},
	journal = {Nature},
	volume = {618},
	number = {7963},
	year = {2023},
	note = {Gong, Grace QBilanges, BenoitAllsop, BenMasson, Glenn RRoberton, VictoriaAskwith, TrevorOxenford, SallyMadsen, Ralitsa RConduit, Sarah EBellini, DomFitzek, MartinaCollier, MattNajam, OsmanHe, ZhenheWahab, BenMcLaughlin, Stephen HChan, A W EdithFeierberg, IsabellaMadin, AndrewMorelli, DanieleBhamra, AmandeepVinciauskaite, VanesaAnderson, Karen ESurinova, SilviaPinotsis, NikosLopez-Guadamillas, ElenaWilcox, MatthewHooper, AlicePatel, ChandniWhitehead, Maria ABunney, Tom DStephens, Len RHawkins, Phillip TKatan, MatildaYellon, Derek MDavidson, Sean MSmith, David MPhillips, James BAngell, RichardWilliams, Roger LVanhaesebroeck, BartengMC_PC_15063/MRC_/Medical Research Council/United KingdomMC_PC_18063/MRC_/Medical Research Council/United KingdomMC_PC_16063/MRC_/Medical Research Council/United KingdomA20265/CRUK_/Cancer Research UK/United KingdomMC_U105184308/MRC_/Medical Research Council/United Kingdom220464/WT_/Wellcome Trust/United Kingdom25722/CRUK_/Cancer Research UK/United KingdomMC_PC_17202/MRC_/Medical Research Council/United KingdomMC_PC_16087/MRC_/Medical Research Council/United KingdomEnglandNature. 2023 Jun;618(7963):159-168. doi: 10.1038/s41586-023-05972-2. Epub 2023 May 24.},
	month = {Jun},
	pages = {159-168},
	edition = {2023/05/25},
	abstract = {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 PI3Kalpha isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kalpha through a distinct mechanism by enhancing multiple steps of the PI3Kalpha catalytic cycle and causes both local and global conformational changes in the PI3Kalpha structure. This compound is selective for PI3Kalpha 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 PI3Kalpha 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 = {*Nerve Regeneration/drug effects, Animals, Biocatalysis/drug effects, Cardiotonic Agents/pharmacology, Cell Proliferation/drug effects, Class I Phosphatidylinositol 3-Kinases/chemistry/drug effects, Humans, Neoplasms/drug therapy, Nerve Crush, Neurites/drug effects, Protein Conformation/drug effects, Protein Isoforms/agonists, Reperfusion Injury/prevention \& control, Signal Transduction/drug effects},
	isbn = {1476-4687 (Electronic)0028-0836 (Print)0028-0836 (Linking)},
	author = {Gong, G. Q. and Bilanges, B. and Allsop, B. and Masson, G. R. and Roberton, V. and Askwith, T. and Oxenford, S. and Madsen, R. R. and Conduit, S. E. and Bellini, D. and Fitzek, M. and Collier, M. and Najam, O. and He, Z. and Wahab, B. and McLaughlin, S. H. and Chan, A. W. E. and Feierberg, I. and Madin, A. and Morelli, D. and Bhamra, A. and Vinciauskaite, V. and Anderson, K E and Surinova, S. and Pinotsis, N. and Lopez-Guadamillas, E. and Wilcox, M. and Hooper, A. and Patel, C. and Whitehead, M. A. and Bunney, T. D. and Stephens, L. R. and Hawkins, P. T. and Katan, M. and Yellon, D. M. and Davidson, S. M. and Smith, D. M. and Phillips, J. B. and Angell, R. and Williams, R. L. and Vanhaesebroeck, B.}
}
