Design, synthesis and biological evaluation of a selective PI3Kγ proteolysis targeting chimera degrader

Phosphatidylinositol 3-kinase γ (PI3Kγ) is a key regulator of tumor progression and a promising therapeutic target for solid tumors and hematological malignancies such as leukemia. However, conventional inhibitors targeting PI3Kγ often suffer from poor isoform selectivity and drug resistance. Proteolysis-targeting chimeras (PROTACs) represent an effective strategy for targeted protein degradation. Herein, a series of PROTACs targeting PI3K were designed and synthesized. Among them, compound P311 exhibited marked degradation activity against p110γ, with DC₅₀ values of 0.82 μM in A2780 cells and 2.06 μM in THP-1 cells, and possessed great isoform selectivity. Mechanistic studies revealed that P311 induced p110γ degradation through the ubiquitin-proteasome pathway. Additionally, P311 markedly suppressed cell proliferation in multiple cancer cell lines. These findings suggested P311, as an efficient selective degrader of PI3Kγ, may have a potential application for tumor therapy.