2. Academic Validation
  3. Discovery of Novel Hydrazide-Based HDAC3 Inhibitors as Epigenetic Immunomodulators for Cancer Immunotherapy

Discovery of Novel Hydrazide-Based HDAC3 Inhibitors as Epigenetic Immunomodulators for Cancer Immunotherapy

  • J Med Chem. 2025 Feb 13;68(3):3048-3064. doi: 10.1021/acs.jmedchem.4c02296.
Zhiqiang Sun 1,  Jinmei Cheng 2,  Chenglong Xu 1,  Xuewen Zhang 1,  Qinru Zang 1,  Xixiang Yang 1,  Yueyu He 1,  Aiqi Su 1,  Xiaopeng Peng 3,  Jianjun Chen 1
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2 Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510515, China.
  • 3 Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Province Key Laboratory of Biomaterials and Biofabrication for Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou 314000, China.
PMID: 39847509 DOI: 10.1021/acs.jmedchem.4c02296
Abstract

Based on our previous work, a series of imidazole-based small molecules were designed and synthesized as HDAC3 inhibitors. Among them, compound SC26 showed selective HDAC3 inhibition activity with an IC50 of 53 nM (SI = 75 for HDAC3 over HDAC1). Further studies revealed that SC26 could dose-dependently induce the expression of PD-L1 in MC38 cells by activating the PD-L1 transcription. SC26 also showed high in vivo antitumor efficacy in a colorectal Cancer model (50 mg/kg po, TGI = 63%). Importantly, the combination of SC26 with the PD-L1 inhibitor NP19 activated the immune system in tumor-bearing mice, enhancing the antitumor immune response (TGI = 80%, 50 + 50 mg/kg, p.o.). Collectively, we report for the first time that an HDAC3 Inhibitor could upregulate PD-L1 expression in vitro and in vivo, specifically in MC38 cells and MC38-bearing tumors, and SC26 represents a novel epigenetic immunomodulator with potential applications in tumor immunotherapy.

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