Authors
Oscar Vadas, Simon Tiede, Maria Chaouki, Laura Tesmer, Shanlin Rao, Rémy Visentin, Ulrich Grädler, Martin Augustin, Reiner Kiefersauer, Carola Gößer, Anne Quillet-Mary, Loïc Ysebaert, Julie Guillermet-Guibert, Lars van der Veen, Giusy Di Conza, Gerhard Hummer
Published in
Nature communications. Volume 17. Issue 1. Oct 09, 2026. Epub Oct 09, 2026.
Abstract
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 key cellular functions, imposing the need to generate isoform-specific inhibition for therapeutic intervention. Roginolisib is a selective PI3Kδ inhibitor that shows promise for the treatment of cancer. Using a combination of X-ray crystallography, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry, we describe the mechanism driving roginolisib's potent and isoform-selective inhibition of PI3Kδ. Roginolisib uniquely stabilises the catalytic C-terminal helix kα12, locking the enzyme in an inactive conformation. This binding mode also results in more sustained inhibition of phosphatidylinositol 3,4,5-trisphosphate formation in tumour samples of CLL patients. Inhibition of PI3Ks by stabilization of helix kα12 into an inactive conformation has not, to the best of our knowledge, been described before and may provide the basis for novel, more selective and effective pharmacological strategies.
PMID:
42855469
Bibliographic data and abstract were imported from PubMed on 10 Oct 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 3
- Comments 0