Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 11, Pages 2174-2181Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00294
Keywords
BRD4 inhibitors; colorectal cancer; bivalent ligands; epigenetics
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Funding
- Natural Science Foundation of Jiangsu Province [BK 20141349]
- China National Key HiTech Innovation Project for the R&D of Novel Drugs [2013ZX09301303-002]
- China Scholarship Council [201907060014]
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Bromodomain-containing protein 4 (Brd4) plays a critical regulatory role in gene transcription that has been recently recognized as a promising strategy for cancer therapy. Based on the BRD4 protein containing two tandem bromodomain structures, BD1 and BD2, we designed and synthesized a series of 3,5-dimethylisoxazole derivative dimers targeting both bromodomains simultaneously to enhance protein binding potency. Among them, compound 22 significantly inhibited the proliferation of colorectal cancer cells HCT116 (IC50 = 162 nM), with a 20-fold increase in antiproliferative activity compared to inhibitor 14. The results of WesternBlot showed that compound 22 could down-regulate c-MYC protein levels and up-regulate HEXIM1 expression and modulate apoptosis through intrinsic pathways. In addition, compound 22 exhibited outstanding antitumor efficacy in the CT-26 tumor mouse model with a tumor suppression rate of 56.1%. Taken together, 3,5-dimethylisoxazole derivative dimer 22 has remarkable protein inhibitory effect and antitumor activity in vitro and in vivo. A protein binding model of compound 22 is being further analyzed, which will facilitate the development of bivalent BRD4 inhibitors and probe the biological function of BRD4.
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