TY - JOUR
T1 - Engineering selective PI3Kγ inhibitors with antitumor and immunomodulatory potentials
AU - Zuo, Yi
AU - Pu, Yiru
AU - Liu, Jianan
AU - Chen, Hongyu
AU - Chen, Yao
AU - Li, Xinlan
AU - Wang, Yan
AU - Zhang, Tingting
AU - Cheng, Hongbin
AU - Liu, Jin
AU - Deng, Yun
AU - Cong, Zhaotong
AU - Wang, Maolin
AU - Lu, Jun
AU - Chen, Shilin
N1 - Funding information:
This study was supported by the National Natural Science Foundation of China (82273812), the Sichuan Outstanding Youth Fund Project (23NSFJQ0099 and 2023NSFSC1932, China), the Chengdu Science and Technology Bureau (2024-YF05-02599-SN, China), the Central Funds Guiding the Local Science and Technology Development of Sichuan Province (2024ZYD0090, China), the Sichuan Science and Technology Program (2024YFFK0172, China), the Guangdong Basic and Applied Basic Research Foundation (2024A1515030013, China), and the Shenzhen Commission of Science and Innovation programs (JCYJ20200109105613463, China).
Publisher Copyright:
© 2025 The Authors.
PY - 2025/11/13
Y1 - 2025/11/13
N2 - 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.
AB - 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.
KW - Immunomodulation
KW - Indole-hybrid aromatic ring
KW - Machine learning
KW - Melanoma treatment
KW - Molecular hybridization
KW - PI3K/AKT/NF-κB signaling axis
KW - PI3Kγ-targeted inhibitor
KW - Tumor-associated macrophage reprograming
UR - https://www.scopus.com/pages/publications/105025221654
U2 - 10.1016/j.apsb.2025.11.011
DO - 10.1016/j.apsb.2025.11.011
M3 - Journal article
AN - SCOPUS:105025221654
SN - 2211-3835
JO - Acta Pharmaceutica Sinica B
JF - Acta Pharmaceutica Sinica B
ER -
