Roginolisib stabilizes inactive PI3Kdelta to deliver specific target blockade with reduced immune toxicity

Phosphoinositide 3-kinase (PI3K) is a key target in cancer therapy, but first-generation PI3K inhibitors were associated with toxicities limiting their clinical use. Roginolisib, a next-generation PI3Kdelta inhibitor, is currently being investigated across multiple cancer types. In contrast to previous PI3K inhibitors, roginolisib has shown a well-tolerated profile. We hypothesize that this improved safety is in part due to high selectivity, driven by its structural properties. Structural and biophysical analyses-including X-ray crystallography, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry-demonstrate that roginolisib, unlike the first-generation inhibitor idelalisib, stabilizes the catalytic C-terminal helix (k-alpha12) of PI3Kdelta. This stabilization is specific for PI3Kdelta and locks the enzyme in an inactive conformation, resulting in potent and sustained inhibition of PI3Kdelta activity. This inhibition profile is observed in tumor samples from patients with chronic lymphocytic leukemia (CLL) and in lymphoma cell lines. Although roginolisib and idelalisib exhibit similar potency in CLL cells, their effects on immune cells differ. Notably, high concentrations of idelalisib impair the cytotoxic activity of CD8 + T cells and promote the differentiation of CD4 + T cells towards Th17 and Th2 subsets. By contrast, roginolisib preserves CD8 + T-cell function and does not alter CD4+ T-cell differentiation. This mechanism of inhibition, likely based on conformational stabilization of the inactive kinase, is novel for PI3K small-molecule inhibitors. Hence, our findings may enable the development of more effective and better-tolerated PI3K inhibitors.