College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Eur J Med Chem. 2020 Apr 1;191:112143. doi: 10.1016/j.ejmech.2020.112143. Epub 2020 Feb 17.
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 (IC = 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 GI 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.
在此，我们交流了我们最近在药物化学方面的努力，这些努力最终产生了一系列结构上具有七元螺环间隔基的 PI3Kδ/γ 双重抑制剂。其中，化合物 26 是最有效的一种，其对 PI3Kδ 的抑制活性（IC=1.0 nM）优于已批准的 PI3Kδ 抑制剂idelalisib。此外，它对人恶性 B 细胞系 SU-DHL-6 表现出显著的抗增殖作用，GI 值为 33 nM。对其他三种 I 类 PI3K 同工型的生化测定表明，化合物 26 是一种有效的 PI3Kδ/γ 双重抑制剂，对 PI3Kα 和 PI3Kβ 具有相当的选择性。在 SU-DHL-6 细胞中，化合物 26 在低至 10 nM 的浓度下即可显著下调 PI3K 信号。令人鼓舞的是，在 Sprague-Dawley（SD）大鼠中的药代动力学（PK）研究表明，它具有口服生物利用度良好（F=87.5%）。总的来说，化合物 26 作为一种有前途的 PI3Kδ/γ 双重抑制剂，在经过广泛的功能研究后，有可能成为治疗白细胞介导的恶性肿瘤的临床候选药物。
