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.同时抑制磷脂酰肌醇3-激酶δ（PI3Kδ）与溴结构域和额外末端结构域（BET），可对B细胞受体信号通路产生协同抑制效应，为侵袭性弥漫大B细胞淋巴瘤（DLBCL）的治疗提供了全新策略。本研究采用融合药效团策略，发现了一系列噻吩并[3,2-d]嘧啶类衍生物，作为首款双功能PI3Kδ-BET抑制剂。经过优化筛选，我们鉴定得到高活性化合物10b：其对PI3Kδ的半数抑制浓度（IC50）为112 ± 8 nM，对BRD4-BD1的半数抑制浓度为19 ± 1 nM，兼具优异且均衡的抑制活性，并在弥漫大B细胞淋巴瘤细胞中展现出强大的抗增殖能力。值得注意的是，相较于其他激酶，该化合物对PI3Kδ展现出良好的选择性，且对正常细胞的细胞毒性极低。此外，化合物10b在小鼠体内具备优良的口服药代动力学特性，并在SU-DHL-6异种移植模型中取得了突出的抗肿瘤活性。综上，通过双功能抑制剂同时靶向PI3Kδ与BET，是治疗弥漫大B细胞淋巴瘤的极具前景的策略。