Design, synthesis, and biological evaluation of a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon modulators

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 37; no. 1; pp. 1715 - 1723
• Main Authors: Liu, Yilin, Song, Yuming, Xu, Yingju, Jiang, Meixu, Lu, Haibin
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01-12-2022; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Anticancer; Antineoplastic Agents - pharmacology; Apoptosis; Cancer; Cell cycle; Cell Line, Tumor; Cell lines; Cell Proliferation; CRBN; Drug Screening Assays, Antitumor; Fluorescence resonance energy transfer; Growth factors; Humans; IMiDs; Investigations; Isoquinolines; Lipopolysaccharides; NCI-H929; Pharmacy; Research Paper; Structure-Activity Relationship; Toxicity; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; NCI-H929; CRBN; Anticancer; IMiDs
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2022.2087219

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 (IC
50
=2.25 µM) and U239 (IC
50
=5.86 µM) cell lines. Compound 10a also can inhibit the TNF-α level (IC
50
=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 (IC
50
=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.