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HDAC8 is a therapeutic target with great promise for breast cancer. Here, we reported a novel compound corallorazine D from Nocardiopsissp. XZB108, selectively inhibited HDAC8 (IC50= 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 5kwas at least 439-fold, superior to corallorazine D, confirming the efficacy of our modifications. In an orthotopic mouse model of breast cancer, 5kdisplayed nearly 4-fold superior antitumor activity than SAHA. Furthermore, 5ktriggered antitumor immunity by activating T cells. Treatment with 5ksignificantly increased the proportion of M1 macrophages and decreased the proportion of M2 macrophages (M1/M2 ratio = 2.67 ± 0.25). 5krepresents a promising compound for further investigation as a potential treatment for breast cancer.