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PXD037721 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleHDX-MS of Activators and Inhibitors of PI3Kalpha
DescriptionHarnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development. This also applies to the PI 3-kinase (PI3K) signalling pathway which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation1-3. Here we report on the discovery of UCL-TRO-1938 (further referred to as 1938), a small molecule activator of the PI3Kα isoform, a critical effector of growth factor signalling. 1938 allosterically activates PI3Kα through a unique 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 PI3Ka 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, upon local administration, enhances nerve regeneration following nerve crush. This study identifies a unique chemical tool to directly probe PI3Kα signalling and a novel 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.
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListNo PTMs are included in the dataset
InstrumentSELECT SERIES Cyclic IMS
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-10-26 00:57:54ID requested
12023-03-06 13:08:47announced
22023-06-08 08:25:50announced2023-06-08: Updated project metadata.
Publication List
Gong GQ, Bilanges B, Allsop B, Masson GR, Roberton V, Askwith T, Oxenford S, Madsen RR, Conduit SE, Bellini D, Fitzek M, Collier M, Najam O, He Z, Wahab B, McLaughlin SH, Chan AWE, Feierberg I, Madin A, Morelli D, Bhamra A, Vinciauskaite V, Anderson KE, Surinova S, Pinotsis N, Lopez-Guadamillas E, Wilcox M, Hooper A, Patel C, Whitehead MA, Bunney TD, Stephens LR, Hawkins PT, Katan M, Yellon DM, Davidson SM, Smith DM, Phillips JB, Angell R, Williams RL, Vanhaesebroeck B, activator for cardioprotection and neuroregeneration. Nature, 618(7963):159-168(2023) [pubmed]
Keyword List
ProteomeXchange project tag: Hydrogen Deuterium Exchange (HDX-MS)
submitter keyword: PI3Ka, UCL-1938-TRO, HDX-MS, p110a
Contact List
contact affiliationUniversity of Dundee
contact emailgmasson001@dundee.ac.uk
lab head
contact affiliationUniversity of Dundee
contact emailgmasson001@dundee.ac.uk
dataset submitter
Full Dataset Link List
Dataset FTP location
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