TPH-104

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.

GPR119 is a promising therapeutic target for type 2 diabetes because of its role in enhancing glucose-stimulated insulin secretion and GLP-1 release. We investigated the anti-diabetic and anti-obesity effects of HG043, a novel and potent thienopyrimidine-based GPR119 agonist, by comparing its pharmacological activities to those of MBX-2982 (a known GPR119 agonist) and sibutramine (an appetite suppressant) in both in vitro and in vivo models. HG043 exhibited potent agonistic activity for human GPR119 and demonstrated enhanced efficacy compared to MBX-2982 in stimulating incretin secretion in pancreatic β-cell lines. Single and long-term treatment with HG043 resulted in significant improvements in diabetic and obesity parameters compared to both MBX-2982 and sibutramine in both healthy and disease models. Furthermore, HG043 demonstrated synergistic glucose-lowering effects when combined with metformin or sitagliptin. These findings suggest that HG043 may serve as a promising therapeutic option for the treatment of type 2 diabetes with obesity patients.