Selective HDAC3 Inhibitors with Potent In Vivo Antitumor Efficacy against Triple-Negative Breast Cancer.
J Med Chem
; 66(17): 12033-12058, 2023 09 14.
Article
in En
| MEDLINE
| ID: mdl-37660352
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Triple Negative Breast Neoplasms
Limits:
Animals
/
Humans
Language:
En
Journal:
J Med Chem
Year:
2023
Document type:
Article