Optimization of Thienopyrimidine Derivatives as Potent and Selective PI3Kδ Inhibitors for Cancer Immunotherapy

作者：Songwen Lin, Nan Xiang, Wenqian Liu, Deyu Wu, Yiran Chen, Tianning Xiong, Jing Ge, Wen Zhou, Hua Tian, Kehui Zhang, Sheng Li, Jing Jin, Hongbo Wang, Heng Xu · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c01036 · 被引用次数：5 · 研究领域：Chronic Lymphocytic Leukemia Research、Immune Cell Function and Interaction、PI3K/AKT/mTOR signaling in cancer

Phosphoinositide 3-kinase δ (PI3Kδ) exerts a pivotal influence on tumor microenvironment, emphasizing its significance in cancer immunotherapy. Herein, a series of novel thienopyrimidine derivatives was designed as potent and selective PI3Kδ inhibitors. Extensive structure–activity relationship studies yielded two lead compounds 18 and 42 with remarkable single-digit nanomolar potencies against PI3Kδ and over 100-fold selectivity relative to other class-I PI3K isoforms. 18 and 42 efficiently inhibited AKT Ser473 phosphorylation in the time- and concentration-dependent manner in mouse B16F10 cells. Mechanistic investigations revealed that 18 and 42 directly suppressed Treg cells and downregulated the expression of PD-L1 in the in vitro settings. With favorable pharmacokinetic properties, 18 underwent further evaluation in B16F10 melanoma and Lewis lung carcinoma mouse models, demonstrating significant in vivo anticancer efficacy by reducing tumor-infiltrating Treg cells and thereby enhancing immune responses. This study collectively highlights the potential of PI3Kδ selective inhibitors as promising candidates toward cancer immunotherapy.