PXD071872-1

PXD071872 is an original dataset announced via ProteomeXchange.

Title	PI3Kdelta is selectively inhibited by roginolisib through stabilizing of the C-terminal helix ka12
Description	Phosphoinositide 3-kinases (PI3Ks) are major regulators of cell growth, proliferation and signalling, constituting key therapeutic targets in cancer, inflammation, and other diseases. Individual class I PI3K isoforms control non-redundant cellular functions, imposing the need to generate isoform-specific inhibition for therapeutic intervention. Roginolisib is a selective PI3Kδ inhibitor that shows great promises for the treatment of cancer. Using a combination of X-ray crystallography, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry, we have uncovered the mechanism driving potent and isoform-selective inhibition of PI3Kδ. Upon occupying the ATP binding site, roginolisib uniquely stabilises the catalytic C-terminal helix kα12, hereby locking the enzyme in an inactive conformation and interfering with membrane targeting of PI3Kδ. This binding mode also results in more sustained inhibition of PIP3 formation in CLL patient samples. We thus uncovered a distinct new mode of PI3K inhibition that is anticipated to inform the rational design of next-generation, more selective and effective pharmacological strategies.
HostingRepository	PRIDE
AnnounceDate	2026-06-24
AnnouncementXML	Submission_2026-06-24_08:06:18.972.xml
DigitalObjectIdentifier	https://doi.org/10.6019/PXD071872
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Oscar Vadas
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-11 06:32:11	ID requested
⏵ 1	2026-06-24 08:06:19	announced

10.6019/PXD071872;

ProteomeXchange project tag: Hydrogen Deuterium Exchange (HDX-MS), Biology/Disease-Driven Human Proteome Project (B/D-HPP)

submitter keyword: phosphoinositide 3-kinase, structure, PI3K, roginolisib, HDX-MS,Lipid signalling, inhibition

Oscar Vadas
contact affiliation	University of Geneva, Faculty of Medicine, Protein Biochemistry Platform, Geneva, Switzerland
contact email	oscar.vadas@unige.ch
lab head
Oscar Vadas
contact affiliation	University of Geneva, Faculty of Medicine
contact email	oscar.vadas@unige.ch
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD071872
     1. Label: PRIDE project
     2. Name: PI3Kdelta is selectively inhibited by roginolisib through stabilizing of the C-terminal helix ka12