Novel Hydrazide-Based HDAC3 Inhibitor Shows Promise in Cancer Treatment

Investigators at Gannan Medical University in the People's Republic of China have discovered a novel hydrazide-based HDAC3 inhibitor, compound 8ae, which demonstrates potent HDAC3 inhibitory activity and significant antiproliferative activity against five types of cancer cells. The compound also exhibits favorable pharmacokinetic properties and has been shown to enhance the immune response in melanoma-bearing mice when combined with a PD-L1 inhibitor.

Key Takeaways:

• Compound 8ae has an IC50 value of 311 nM and a selectivity index SI greater than 32 over other HDACs, indicating potent HDAC3 inhibitory activity.
• The compound demonstrates significant antiproliferative activity against five types of cancer cells, with an average inhibitory rate IC50 value of 5.036 μM.
• Compound 8ae is capable of inhibiting the migration, invasion, and wound healing activities of B16-F10 cells.
• The compound effectively modulates the expression of Ac-H3 within tumor cells and can degrade PDL1 in tumor cells through the lysosome pathway mediated by cathepsin B (CTSB).
• In in vivo experiments, the combination of 8ae with the PD-L1 inhibitor NP-19 activated the immune system in melanoma-bearing mice, leading to an enhanced anti-tumor immune response (TGI = 65%).
• When combined with olaparib, 8ae significantly enhanced tumor suppressive activity (TGI = 88%) in a breast cancer mouse model and displayed a favorable safety profile.
• Financial supporters for this research include the National Natural Science Foundation of China (NSFC), Jiangxi Provincial Natural Science Foundation, Science and Technology Projects of Ganzhou, and Start-Up Foundation of Gannan Medical University.
• Additional researchers involved include Zhihao Hu, Shuqing Li, Wanyi Pan, and Haiyan Wu.

Statistics:

• IC50 value of compound 8ae: 311 nM
• Selectivity index SI of compound 8ae: greater than 32
• Average inhibitory rate IC50 value of compound 8ae against five types of cancer cells: 5.036 μM
• Enhanced anti-tumor immune response in melanoma-bearing mice: 65%
• Tumor suppressive activity in breast cancer mouse model when combined with olaparib: 88%

Sources:

• "Design, Synthesis and Bioevaluation of Novel Hydrazide Derivatives As Enhancers of Immunotherapy and Dna-damage Response In Antitumor Therapy." European Journal of Medicinal Chemistry, vol. 291, 2025.
• NewsRx. "Data on Cancer Reported by Researchers at Gannan Medical University (Design, Synthesis and Bioevaluation of Novel Hydrazide Derivatives As Enhancers of Immunotherapy and Dna-damage Response In Antitumor Therapy)." Immunotherapy Weekly, July 9, 2025, p. 857.
• Gannan Medical University, Ministry of Education, Key Lab Prevent & Treatment Cardiovasc & Cerebrova, College of Pharmacy, Jiangxi Prov Key Lab Tissue Engn 2024SS, Ganzhou 314000, People's Republic of China (Corresponding author: Xiaopeng Peng)
• Elsevier - www.elsevier.com; European Journal of Medicinal Chemistry - www.journals.elsevier.com/european-journal-of-medicinal-chemistry/