Abstract

In the current study, we designed and synthesised a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon (CRBN) modulators. The results of the CCK8 assay revealed potent antiproliferative activity for the selected compound 10a against NCI-H929 (IC₅₀=2.25 µM) and U239 (IC₅₀=5.86 µM) cell lines. Compound 10a also can inhibit the TNF-α level (IC₅₀=0.76 µM) in LPS stimulated PMBC and showed nearly no toxicity to this normal human cell line. The TR-FRET assay showed compound 10a having potent inhibitory activity against CRBN (IC₅₀=4.83 µM), and the docking study confirmed a nice fitting of 10a into the active sites of CRBN. Further biology studies revealed compound 10a can increase the apoptotic events, arrest the NCI-H929 cells at G0/G1 cell cycle, and induce the ubiquitination degradation of IKZF1 and IKZF3 proteins by CRL4^CRBN. These preliminary results suggested that compound 10a could serve as a potential antitumor drug and worthy of further investigation.

摘要

在目前的研究中，我们设计并合成了一系列新的 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2 H ,4 H )-二酮衍生物作为 cereblon (CRBN) 调节剂。CCK8 测定的结果显示所选化合物10a对 NCI-H929 (IC ₅₀ =2.25 µM) 和 U239 (IC ₅₀ =5.86 µM) 细胞系具有有效的抗增殖活性。化合物10a还可以抑制 LPS 刺激的 PMBC 中的 TNF-α 水平 (IC ₅₀ =0.76 µM)，并且对这种正常人细胞系几乎没有毒性。TR-FRET 分析显示化合物10a对 CRBN 具有强效抑制活性（IC ₅₀= 4.83 µM），对接研究证实10a很好地适合CRBN 的活性位点。进一步的生物学研究表明，化合物10a可以增加凋亡事件，将 NCI-H929 细胞阻滞在 G0/G1 细胞周期，并通过 CRL4 ^CRBN诱导 IKZF1 和 IKZF3 蛋白的泛素化降解。这些初步结果表明化合物10a可以作为一种潜在的抗肿瘤药物，值得进一步研究。