Institute of Marine Biology and Pharmacology, Ocean College, Zhejiang University, Zhoushan 316021, China.
Key Laboratory of Digestive Pathophysiology of Zhejiang Province, the First Affiliated Hospital of Zhejiang Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China.
J Med Chem. 2024 Aug 22;67(16):14609-14632. doi: 10.1021/acs.jmedchem.4c01438. Epub 2024 Aug 7.
HDAC8 is a therapeutic target with great promise for breast cancer. Here, we reported a novel compound corallorazine D from sp. XZB108, selectively inhibited HDAC8 (IC = 0.90 ± 0.014 μM), suggesting that it may be a promising nonhydroxamate HDAC8 inhibitor. Upon additional modifications of corallorazine D, a candidate compound , demonstrated remarkable inhibitory potency against HDAC8 (IC = 0.12 ± 0.01 nM), 89-fold superior to PCI-34051. The selectivity of was at least 439-fold, superior to corallorazine D, confirming the efficacy of our modifications. In an orthotopic mouse model of breast cancer, displayed nearly 4-fold superior antitumor activity than SAHA. Furthermore, triggered antitumor immunity by activating T cells. Treatment with significantly increased the proportion of M1 macrophages and decreased the proportion of M2 macrophages (M1/M2 ratio = 2.67 ± 0.25). represents a promising compound for further investigation as a potential treatment for breast cancer.
HDAC8 是乳腺癌极具前景的治疗靶点。在这里，我们报道了一种来自 sp. XZB108 的新型化合物珊瑚嗪 D，它选择性地抑制 HDAC8（IC = 0.90 ± 0.014 μM），表明它可能是一种有前途的非羟肟酸 HDAC8 抑制剂。在对珊瑚嗪 D 进行进一步修饰后，候选化合物 对 HDAC8 表现出显著的抑制活性（IC = 0.12 ± 0.01 nM），比 PCI-34051 强 89 倍。的选择性至少比珊瑚嗪 D 高 439 倍，证实了我们修饰的效果。在乳腺癌的原位小鼠模型中， 显示出比 SAHA 强近 4 倍的抗肿瘤活性。此外， 通过激活 T 细胞触发抗肿瘤免疫。用 治疗显著增加了 M1 巨噬细胞的比例，降低了 M2 巨噬细胞的比例（M1/M2 比值 = 2.67 ± 0.25）。 作为一种潜在的乳腺癌治疗药物，具有很大的研究潜力。
