2. Academic Validation
  3. Selective HDAC3 Inhibitors with Potent In Vivo Antitumor Efficacy against Triple-Negative Breast Cancer

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

  • J Med Chem. 2023 Sep 14;66(17):12033-12058. doi: 10.1021/acs.jmedchem.3c00614.
Sravani Pulya 1,  Ambati Himaja 1,  Milan Paul 2,  Nilanjan Adhikari 3,  Suvankar Banerjee 3,  Ganesh Routholla 1,  Swati Biswas 2,  Tarun Jha 3,  Balaram Ghosh 1
Affiliations

Affiliations

  • 1 Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad 500078, India.
  • 2 Nanomedicine Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad 500078, India.
  • 3 Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P.O. Box 17020, Kolkata, West Bengal 700032, India.
PMID: 37660352 DOI: 10.1021/acs.jmedchem.3c00614
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.

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