PXD037721-3

PXD037721 is an original dataset announced via ProteomeXchange.

Title	HDX-MS of Activators and Inhibitors of PI3Kalpha
Description	Harnessing 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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:48:41.244.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Glenn Masson
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	SELECT SERIES Cyclic IMS

Revision	Datetime	Status	ChangeLog Entry
0	2022-10-26 00:57:54	ID requested
1	2023-03-06 13:08:47	announced
2	2023-06-08 08:25:50	announced	2023-06-08: Updated project metadata.
⏵ 3	2023-11-14 08:48:42	announced	2023-11-14: Updated project metadata.

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]

ProteomeXchange project tag: Hydrogen Deuterium Exchange (HDX-MS)

submitter keyword: PI3Ka, UCL-1938-TRO, HDX-MS, p110a

Glenn Masson
contact affiliation	University of Dundee
contact email	gmasson001@dundee.ac.uk
lab head
Glenn Masson
contact affiliation	University of Dundee
contact email	gmasson001@dundee.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/03/PXD037721

PRIDE project URI

• PRIDE
  1. PXD037721
     1. Label: PRIDE project
     2. Name: HDX-MS of Activators and Inhibitors of PI3Kalpha