Targeting PI3Kδ for lymphoma and immune diseases treatment: a review.

Phosphatidylinositol 3-kinase delta (PI3Kδ) is a member of the class I PI3Ks. Its abnormal expression is closely related to the occurrence and development of tumors and immune diseases. Inhibiting PI3Kδ is an effective method for treating such diseases. The recently approved targeted therapeutics have demonstrated that PI3Kδ inhibitors yield substantial clinical benefits for patients with lymphoma and immunological disorders. For example, linperlisib has a lower risk of market-withdrawal-level safety issues compared with umbralisib, and has more manageable risks of adverse events including diarrhea compared with idelalisib and duvelisib. In contrast to other PI3Kδ inhibitors of the same class, it exerts superior therapeutic efficacy in T-cell lymphoma (TCL), thereby providing a novel treatment option for TCL patients. In addition, several agents with distinctive mechanisms of action have shown promising outcomes and are expected to enter clinical practice in the next few years, such as zandelisib featuring a long-acting mechanism and proteolysis-targeting chimeras (PROTAC)-based PI3Kδ degrader B14. Although PI3Kδ inhibitors confer notable benefits on patients, adverse effects remain a key factor limiting their extensive clinical application. Hence, developing PI3Kδ inhibitors with high selectivity and favorable safety profiles, as well as exploring rational medication strategies for these inhibitors, remains a major research focus at present. In this review, we briefly introduce PI3Kδ and its roles in tumors and immune diseases, summarize the clinical trial results, synthetic routes and structural characteristics of representative PI3Kδ inhibitors, and provide recommendations for the development and application of PI3Kδ inhibitors.