Herein, we communicate our recent medicinal chemistry efforts which have culminated in a series of PI3Kδ/γ dual inhibitors structurally featuring a seven-membered spirocyclic spacer. Compound 26, the most potent one among them, exhibited superior PI3Kδ inhibitory activity (IC50 = 1.0 nM) to that of the approved PI3Kδ inhibitor Idelalisib. Besides, it exerted remarkable anti-proliferative efficacy against human malignant B-cell line SU-DHL-6 with GI50 value of 33 nM. The biochemical assay against the other three class I PI3K isoforms identified compound 26 as a potent PI3Kδ/γ dual inhibitor with considerable selectivity over PI3Kα and PI3Kβ. In SU-DHL-6 cells, a dramatic down-regulation of PI3K signaling was observed following compound 26-treatment at the concentration as low as 10 nM. Inspiringly, the pharmacokinetic (PK) study in Sprague-Dawley (SD) rats revealed it was orally available with a favorable bioavailability (F = 87.5%). Overall, compound 26, a promising PI3Kδ/γ dual inhibitor, has the potential to emerge as a clinical candidate for the treatment of leukocyte-mediated malignancies after extensive functional investigation.

中文翻译：

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结构新颖的PI3Kδ/γ双抑制剂，特征在于七元螺环间隔子：SAR研究和PK评估。

在此，我们传达了我们最近的药物化学研究成果，这些研究成果最终达到了一系列PI7Kδ/γ双重抑制剂的结构，这些抑制剂在结构上具有七元螺环间隔基。其中最有效的化合物26表现出比批准的PI3Kδ抑制剂艾达拉西布更好的PI3Kδ抑制活性（IC50 = 1.0 nM）。此外，它对人恶性B细胞系SU-DHL-6具有显着的抗增殖作用，GI50值为33 nM。针对其他三种I类PI3K同工型的生化分析确定化合物26为有效的PI3Kδ/γ双抑制剂，对PI3Kα和PI3Kβ具有相当高的选择性。在SU-DHL-6细胞中，以低至10 nM的浓度进行化合物26处理后，观察到PI3K信号显着下调。鼓舞人心 在Sprague-Dawley（SD）大鼠中进行的药代动力学（PK）研究表明，该药物口服有效，具有良好的生物利用度（F = 87.5％）。总体而言，经过广泛的功能研究，化合物26是一种有前途的PI3Kδ/γ双抑制剂，有潜力成为临床治疗白细胞介导的恶性肿瘤的候选药物。