Phosphoinositide 3-kinase δ (PI3Kδ) plays a critical role in B lymphocyte (B-cell) development and activation and has been a validated target for the treatment of B-cell malignancies. Herein, we report a series of thienopyrimidine derivatives as novel potent and selective PI3Kδ inhibitors based on a scaffold hopping design strategy. Among them, compound 6 exhibited nanomolar PI3Kδ potency and a favorable selectivity profile compared to other class I PI3K isoforms. In cellular assays, compound 6 showed antiproliferative activity against a panel of B-cell lymphoma cell lines in a low micromolar range, caused cell cycle arrest, and induced apoptosis in Pfeiffer and SU-DHL-6 cells. Further, compound 6 inhibited the activation of mouse B-cells. With support from in vivo pharmacokinetic studies, compound 6 demonstrated significant anticancer efficacy in a Pfeiffer xenograft mouse model. Overall, compound 6 is a promising PI3Kδ inhibitor worthy of further preclinical investigation for the treatment of B-cell malignancies.

中文翻译：

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噻吩并嘧啶衍生物作为治疗 B 细胞恶性肿瘤的有效和选择性 PI3Kδ 抑制剂的设计和优化

磷酸肌醇 3-激酶 δ (PI3Kδ) 在 B 淋巴细胞 (B 细胞) 的发育和激活中起关键作用，并且已成为治疗 B 细胞恶性肿瘤的有效靶点。在此，我们报告了一系列噻吩并嘧啶衍生物作为基于支架跳跃设计策略的新型强效和选择性 PI3Kδ 抑制剂。其中，与其他 I 类 PI3K 异构体相比，化合物6表现出纳摩尔级 PI3Kδ 效力和良好的选择性特征。在细胞试验中，化合物6在低微摩尔范围内对一组 B 细胞淋巴瘤细胞系显示出抗增殖活性，在 Pfeiffer 和 SU-DHL-6 细胞中引起细胞周期停滞并诱导细胞凋亡。此外，化合物6抑制小鼠 B 细胞的活化。在体内药代动力学研究的支持下，化合物6在 Pfeiffer 异种移植小鼠模型中显示出显着的抗癌功效。总体而言，化合物6是一种很有前途的 PI3Kδ 抑制剂，值得在治疗 B 细胞恶性肿瘤方面进行进一步的临床前研究。