Engineering selective PI3Kγ inhibitors with antitumor and immunomodulatory potentials.

PI3Kγ 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 PI3Kγ 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 PI3Kγ relative to PI3Kα/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 PI3Kγ/AKT/NF-κB signaling axis. Concurrently, it restrained the M2 polarization of tumor-associated macrophages, thereby augmenting the antitumor immune response. This study underscores the potential for PI3Kγ inhibitors as immunomodulators and direct antitumor agents.