PI3Kδ is selectively inhibited by roginolisib by stabilizing the C-terminal helix kα12
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.
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BibTeX
@article{vadas2026pi3kδ,
title = {{PI3Kδ is selectively inhibited by roginolisib by stabilizing the C-terminal helix kα12}},
author = {Oscar Vadas and Simon Tiede and Maria Chaouki and Laura Tesmer and Shanlin Rao and Rémy Visentin and Ulrich Grädler and Martin Augustin and Reiner Kiefersauer and Carola Gößer and Anne Quillet-Mary and Loïc Ysebaert and Julie Guillermet-Guibert and Lars van der Veen and Giusy Di Conza and Gerhard Hummer},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-77424-0},
url = {https://www.nature.com/articles/s41467-026-77424-0},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - PI3Kδ is selectively inhibited by roginolisib by stabilizing the C-terminal helix kα12
AU - Oscar Vadas
AU - Simon Tiede
AU - Maria Chaouki
AU - Laura Tesmer
AU - Shanlin Rao
AU - Rémy Visentin
AU - Ulrich Grädler
AU - Martin Augustin
AU - Reiner Kiefersauer
AU - Carola Gößer
AU - Anne Quillet-Mary
AU - Loïc Ysebaert
AU - Julie Guillermet-Guibert
AU - Lars van der Veen
AU - Giusy Di Conza
AU - Gerhard Hummer
PY - 2026
DA - 2026/10/09
JO - Nature Communications
DO - 10.1038/s41467-026-77424-0
UR - https://www.nature.com/articles/s41467-026-77424-0
AB - 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.
SN - 2041-1723
ER -