Selective HDAC3 Inhibitors with Potent In Vivo Antitumor Efficacy against Triple-Negative Breast Cancer

HDAC3 modulation shows promise for breast cancer, including
triple-negative
cases. Novel pyrazino-hydrazide-based HDAC3 inhibitors
were designed and synthesized. Lead compound 4i exhibited
potent HDAC3 inhibition (IC50 = 14 nM) with at least 121-fold
selectivity. It demonstrated strong cytotoxicity against triple-negative
breast cancer cells (IC50: 0.55 μM for 4T1, 0.74
μM for MDA-MB-231) with least normal cell toxicity. Metabolically
stable 4i displayed a superior pharmacokinetic profile.
A dose-dependent therapeutic efficacy of 4i was observed
in a tumor-bearing mouse model. The biomarker analysis with tumor
tissues displayed enhanced acetylation on Ac-H3K9, Ac-H3K27, and Ac-H4K12 compared to Ac-tubulin and Ac-SMC3 indicating HDAC3
selectivity of 4i in vivo. The immunoblotting study with
tumor tissue showed upregulation of apoptotic proteins caspase-3,
caspase-7, and cytochrome c and the downregulation
of proliferation markers Bcl-2, CD44, EGFR, and Ki-67. Compound 4i represents a promising candidate for targeted breast cancer
therapy, particularly for cases with triple-negative breast cancer.