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Anti-multiple myeloma potential of resynthesized belinostat derivatives: an experimental study on cytotoxic activity,
Hong Phuong Nguyen1, Quang De Tran2, Cuong Quoc Nguyen2
1Department of Biomedical Science, BK21 FOUR Program in Biomedical Science and Engineering, Inha University College of Medicine Incheon 22212 South Korea sugeun.yang@inha.ac.kr +82-32-890-1199 +82-32-890-2832.
Abstract:
Multiple myeloma is a deadly cancer that is a complex and multifactorial disease. In the present study, 12 belinostat derivatives (four resynthesized and eight new), HDAC inhibitors, were resynthesized via either Knoevenagel condensation, or Wittig reaction, or Heck reaction. Then an evaluation of the antiproliferative activities against myeloma cells MOPC-315 was carried out. Amongst them, compound 7f was the most bioactive compound with an IC50 of 0.090 ± 0.016 μM, being 3.5-fold more potent than the reference belinostat (IC50 = 0.318 ± 0.049 μM). Furthermore, we also confirmed the inhibitory activity of 7f in a cellular model. Additionally, we found that the inhibitory activity of 7f against histone deacetylase 6 catalytic activity (HDAC6) is more potent than that of belinostat. Finally, we observed the strong synergistic interaction between the derivative 7f and the proteasome bortezomib inhibitor (CI = 0.26), while belinostat and bortezomib showed synergism with a CI value of 0.36. Taken together, the above results suggest that 7f is a promising HDAC inhibitor deserving further investigation.
Insights
Researchers developed new HDAC inhibitors to treat multiple myeloma. Compound 7f showed potent anti-myeloma activity and synergistic effects with bortezomib, indicating its potential as a novel cancer therapy.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Multiple myeloma is a complex and fatal hematologic malignancy.
- Histone deacetylase (HDAC) inhibitors represent a therapeutic strategy for multiple myeloma.
- Belinostat is an established HDAC inhibitor used in multiple myeloma treatment.
Purpose of the Study:
- To synthesize and evaluate novel HDAC inhibitors as potential anti-myeloma agents.
- To compare the antiproliferative activity of new derivatives against belinostat.
- To investigate the synergistic effects of the most potent derivative with bortezomib.
Main Methods:
- Synthesis of 12 belinostat derivatives using Knoevenagel condensation, Wittig reaction, or Heck reaction.
- Assessment of antiproliferative activity against MOPC-315 myeloma cells.
- Evaluation of HDAC6 inhibitory activity and drug synergy with bortezomib.
Main Results:
- Compound 7f exhibited the highest antiproliferative activity (IC50 = 0.090 μM), 3.5-fold more potent than belinostat (IC50 = 0.318 μM).
- Compound 7f demonstrated superior inhibition of HDAC6 catalytic activity compared to belinostat.
- Compound 7f showed a strong synergistic interaction with bortezomib (CI = 0.26), exceeding that of belinostat (CI = 0.36).
Conclusions:
- Compound 7f is a highly potent HDAC inhibitor with significant antiproliferative effects against multiple myeloma cells.
- The enhanced potency and synergistic activity of 7f suggest its potential as a promising therapeutic agent for multiple myeloma.
- Further investigation of compound 7f is warranted for its development as a novel cancer therapy.
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