1. Natural Derivatives of Selective HDAC8 Inhibitors with Potent in Vivo Antitumor Efficacy against Breast Cancer.
- Author
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Chen X, Ding X, Fang J, Mao C, Gong X, Zhang Y, Zhang N, Yan F, Lou Y, Chen Z, Ding W, and Ma Z
- Subjects
- Animals, Female, Humans, Mice, Cell Line, Tumor, Repressor Proteins antagonists & inhibitors, Repressor Proteins metabolism, Structure-Activity Relationship, Mice, Inbred BALB C, Cell Proliferation drug effects, Xenograft Model Antitumor Assays, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylase Inhibitors chemical synthesis, Histone Deacetylase Inhibitors chemistry, Histone Deacetylase Inhibitors therapeutic use, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents therapeutic use, Histone Deacetylases metabolism
- Abstract
HDAC8 is a therapeutic target with great promise for breast cancer. Here, we reported a novel compound corallorazine D from Nocardiopsis sp. XZB108, selectively inhibited HDAC8 (IC
50 = 0.90 ± 0.014 μM), suggesting that it may be a promising nonhydroxamate HDAC8 inhibitor. Upon additional modifications of corallorazine D, a candidate compound 5k , demonstrated remarkable inhibitory potency against HDAC8 (IC50 = 0.12 ± 0.01 nM), 89-fold superior to PCI-34051. The selectivity of 5k was at least 439-fold, superior to corallorazine D, confirming the efficacy of our modifications. In an orthotopic mouse model of breast cancer, 5k displayed nearly 4-fold superior antitumor activity than SAHA. Furthermore, 5k triggered antitumor immunity by activating T cells. Treatment with 5k significantly increased the proportion of M1 macrophages and decreased the proportion of M2 macrophages (M1/M2 ratio = 2.67 ± 0.25). 5k represents a promising compound for further investigation as a potential treatment for breast cancer.- Published
- 2024
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