TPH-104

The phosphoinositide-3-kinase-α is a key regulator of tumor progression across different cancers, including triple-negative breast cancer. Herein, we explored thienopyrimidine and pyridofuropyrimidine cores to identify a PI3K-α inhibitor for the treatment of TNBC with favorable ADME properties. Structure-guided drug design and lead optimization efforts led to the identification of piperidine urea analog 50b as a PI3K-α inhibitor, which effectively inhibits the growth of MDA-MB-231 cells by targeting p110α, MAP kinase pathways, enhancing the expression of apoptotic proteins and impeding the cell's migratory capabilities. Compound 50b occupies the PI3K-α hinge pocket and forms H-bonding with VAL851, as well as with GLN859, a nonconserved residue linked to isoform selectivity. It exhibited a favorable ADME/PK profile, with 56% oral bioavailability, and demonstrated efficacy in the MDA-MB-231 xenograft model at peroral doses ranging from 25 to 75 mg/kg. Acute and repeated-dose toxicity studies confirmed an excellent safety profile, suggesting its potential for further development as a lead molecule for TNBC.

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.