Design, Synthesis, and Biological Evaluation of Thieno[3,2-d]pyrimidine Derivatives as the First Bifunctional PI3Kδ Isoform Selective/Bromodomain and Extra-Terminal Inhibitors

The concomitant inhibition of PI3Kδ and bromodomain and extra-terminal (BET) that exerts a synergistic effect on the B-cell receptor signaling pathway provides a new strategy for the treatment of aggressive diffuse large B-cell lymphoma (DLBCL). Herein, a merged pharmacophore strategy was utilized to discover a series of thieno[3,2-d]pyrimidine derivatives as the first-in-class bifunctional PI3Kδ-BET inhibitors. Through optimization, a highly potent compound (10b) was identified to possess excellent and balanced activities against PI3Kδ [inhibitory concentration (IC₅₀) = 112 ± 8 nM] and BRD4-BD1 (IC₅₀ = 19 ± 1 nM) and exhibited strong antiproliferative activities in DLBCL cells. Notably, this compound demonstrated good PI3Kδ selectivity over other kinases with minimal cytotoxicity in normal cells. Moreover, 10b has a good oral pharmacokinetic profile in mice and achieves outstanding antitumor activity in the SU-DHL-6 xenograft model. Taken together, these results indicate that targeting PI3Kδ and BET with a bifunctional inhibitor is a promising strategy to treat DLBCL.