Design and evaluation of potent BRD4 Bromodomain inhibitors based on ZA channel hot spot

doi:10.5246/jcps.2023.12.078

Abstract

Abstract:

Bromodomain, an epigenetic reader module, is garnering increasing interest due to its critical function in recognizing acetylated histones. Bromodomain-containing proteins have been implicated in the development of various diseases, making the targeting of bromodomain a significant strategy for developing protein-protein interaction (PPI) inhibitors. In the present study, a novel hot spot was identified on the ZA channel, which is located in the acetyl lysine binding site of BRD4. To investigate the significance of this hot spot, structure-based drug design was conducted on a 3,5-dimethylisoxazole-based BRD4 inhibitor (4). A series of derivatives were synthesized with structural modifications focusing on the ZA channel hot spot. Through structural optimization, a promising derivative compound 21, was developed, demonstrating nanomolar protein and cell potency. This study suggested that the ZA channel hot spot might play a crucial role in the activity and selectivity of BRD4 inhibitors.

Key words: Protein-protein interactions, BRD4, ZA Channel, Acute myeloid leukemia cell

Supporting:

Huili Li, Jue Li, Dandan He, Ling Tao, Yubing Jiang, Xiangchun Shen, Fei Jiang. Design and evaluation of potent BRD4 Bromodomain inhibitors based on ZA channel hot spot[J]. Journal of Chinese Pharmaceutical Sciences, 2023, 32(12): 971-988.

Figures/Tables 11

Table 1. IC50 and Ki values of compounds 9–24 against BRD4(1) and BRD4(2) using FP assay, respectively (mean ± SD, n = 3).

Table 2. The percentage inhibition of compounds 25–27 against diverse BRDs under 25 μM (mean ± SD, n = 3).

Table 3. Effect of compounds 18, 21, and 24 in cancer cell lines (n = 3).

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