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