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

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.