PI3Kδ is selectively inhibited by roginolisib by stabilizing the C-terminal helix kα12.

Roginolisib selectively inhibits PI3Kδ by stabilizing the C-terminal helix kα12, locking the enzyme in an inactive conformation.

• Why it matters: Targeting specific PI3K isoforms is crucial for developing effective therapies for cancer and other diseases, but mechanisms of isoform selectivity are not fully understood.
• What they did: The study used X-ray crystallography, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry to reveal how roginolisib stabilizes helix kα12, leading to potent and selective inhibition of PI3Kδ.
• The result: This stabilization results in more sustained inhibition of phosphatidylinositol 3,4,5-trisphosphate formation in CLL tumor samples, suggesting a novel approach for designing more selective pharmacological agents.