Upregulation of p53 through induction of MDM2 degradation: Anthraquinone analogs

[Display omitted] In a previous study, a novel anthraquinone analog BW-AQ-101 was identified as a potent inducer of MDM2 degradation, leading to upregulation of p53 and apoptosis in cell culture studies. In animal models of acute lymphocytic leukemia, treatment with BW-AQ-101 led to complete disease...

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Published in:Bioorganic & medicinal chemistry 2019-09, Vol.27 (17), p.3860-3865
Main Authors: Draganov, Alexander B., Yang, Xiaoxiao, Anifowose, Abiodun, De La Cruz, Ladie Kimberly C., Dai, Chaofeng, Ni, Nanting, Chen, Weixuan, De Los Santos, Zeus, Gu, Lubing, Zhou, Muxiang, Wang, Binghe
Format: Article
Language:English
Subjects:
Anthraquinone
Anti-tumor activity
Lymphoblastic leukemia
MDM2 inhibitor
p53 activation
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Summary:[Display omitted] In a previous study, a novel anthraquinone analog BW-AQ-101 was identified as a potent inducer of MDM2 degradation, leading to upregulation of p53 and apoptosis in cell culture studies. In animal models of acute lymphocytic leukemia, treatment with BW-AQ-101 led to complete disease remission. In this study, we systematically investigated the effect of substitution patterns of the core anthraquinone scaffold. Through cytotoxicity evaluation in two leukemia cell lines, the structure-activity relationship of thirty-two analogs has been examined. Several analogs with comparable or improved potency over BW-AQ-101 have been identified. Western-blot assays verified the effect of the potent compounds on the MDM2-p53 axis. The study also suggests new chemical space for further optimization work.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2019.07.019