Discovery of novel PI3KC2γ inhibitors with high potency, selectivity, and favorable pharmacokinetics for glycogen metabolism regulation.

Phosphatidylinositol 3-kinase Class IIγ (PI3KC2γ) is a critical regulator of PI(3,4)P2 production on endosomal membranes, linking its activity to metabolic disorders such as diabetes, glycogen storage diseases, and hyperlipidemia. Despite its importance, selective inhibitors targeting PI3KC2γ remain underexplored. In this study, we developed novel scaffolds for PI3KC2γ inhibitors using structure-based design. A series of inhibitors were synthesized, among which compound 23 was identified as the most potent PI3KC2γ inhibitor reported to date. Functional assays confirmed that compound 23 effectively inhibits insulin-stimulated PI(3,4)P2 formation, blocks glucose-to-glycogen conversion, and reduces excessive liver glycogen accumulation by downregulating the Akt2-glycogen synthase pathway. This study highlights the therapeutic potential of PI3KC2γ inhibition in glycogen storage diseases and provides efficient tool molecules for further drug development.