Engineering selective PI3Kγ inhibitors with antitumor and immunomodulatory potentials

PI3K γ represents a promising therapeutic target for its pivotal role in macrophage recruitment and polarization and its significant association with tumor invasion and metastasis. In this study, a series of novel indole-based PI3K γ selective inhibitors were generated by machine learning combined with molecular hybridization. Intriguingly, the representative IHA-5f displayed picomolar-level potency and highly selective inhibition to PI3K γ relative to PI3K α / β / δ . Moreover, IHA-5f manifested prominent anti-melanoma activity in vitro and in vivo with no detectable visceral toxicity. Mechanistically, IHA-5f efficiently suppressed tumor cell proliferation and migration, and induced apoptosis by suppressing the PI3K γ /AKT/NF- κ B signaling axis. Concurrently, it restrained the M2 polarization of tumor-associated macrophages, thereby augmenting the antitumor immune response. This study underscores the potential for PI3K γ inhibitors as immunomodulators and direct antitumor agents. PI3K γ -specific inhibitors were generated by machine learning combined with molecular hybridization, with representative IHA-5f exhibiting picomolar-level potency. Intriguingly, IHA-5f displayed excellent anti-melanoma effect via PI3K γ inhibition and TMA reprogramming.