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Published on: March 20, 2020
Development of a versatile DNMT and HDAC inhibitor C02S modulating multiple cancer hallmarks for breast cancer
Zigao Yuan1, Shaopeng Chen2, Chunmei Gao3
1Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
Abstract:
DNMT and HDAC are closely related to each other and involved in various human diseases especially cancer. These two enzymes have been widely recognized as antitumor targets for drug discovery. Besides, research has indicated that combination therapy consisting of DNMT and HDAC inhibitors exhibited therapeutic advantages. We have reported a DNMT and HDAC dual inhibitor 15a of which the DNMT enzymatic inhibitory potency needs to be improved. Herein we reported the development of a novel dual DNMT and HDAC inhibitor C02S which showed potent enzymatic inhibitory activities against DNMT1, DNMT3A, DNMT3B and HDAC1 with IC50 values of 2.05, 0.93, 1.32, and 4.16 µM, respectively. Further evaluations indicated that C02S could inhibit DNMT and HDAC at cellular levels, thereby inversing mutated methylation and acetylation and increasing expression of tumor suppressor proteins. Moreover, C02S regulated multiple biological processes including inducing apoptosis and G0/G1 cell cycle arrest, inhibiting angiogenesis, blocking migration and invasion, and finally suppressing tumor cells proliferation in vitro and tumor growth in vivo.
Insights
A novel dual inhibitor, C02S, effectively targets DNA methyltransferase (DNMT) and histone deacetylase (HDAC) enzymes. This compound shows potent anti-cancer activity by inducing apoptosis and inhibiting tumor growth.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- DNA methyltransferase (DNMT) and histone deacetylase (HDAC) enzymes are implicated in human diseases, particularly cancer.
- These enzymes are recognized as key targets for anticancer drug discovery.
- Combination therapy with DNMT and HDAC inhibitors has shown therapeutic benefits.
Purpose of the Study:
- To develop a novel dual inhibitor of DNMT and HDAC with improved potency.
- To evaluate the enzymatic and cellular inhibitory activities of the new compound, C02S.
- To assess the therapeutic potential of C02S in preclinical cancer models.
Main Methods:
- Synthesis and characterization of the novel dual inhibitor C02S.
- Enzymatic assays to determine IC50 values against DNMT1, DNMT3A, DNMT3B, and HDAC1.
- Cellular assays to assess inhibition of DNMT and HDAC, reversal of aberrant methylation and acetylation, and expression of tumor suppressor proteins.
- In vitro and in vivo studies to evaluate effects on apoptosis, cell cycle arrest, angiogenesis, migration, invasion, proliferation, and tumor growth.
Main Results:
- C02S demonstrated potent enzymatic inhibition against DNMT1, DNMT3A, DNMT3B, and HDAC1 (IC50 values: 2.05, 0.93, 1.32, and 4.16 µM, respectively).
- C02S effectively inhibited DNMT and HDAC activity in cells, reversing aberrant methylation and acetylation patterns and upregulating tumor suppressor proteins.
- The compound induced apoptosis, G0/G1 cell cycle arrest, inhibited angiogenesis, and blocked migration and invasion in vitro.
- C02S suppressed tumor cell proliferation in vitro and tumor growth in vivo.
Conclusions:
- C02S is a potent dual DNMT and HDAC inhibitor with significant anticancer properties.
- C02S exerts its antitumor effects through multiple mechanisms, including epigenetic modulation and induction of cell death.
- C02S represents a promising candidate for further development as an anticancer therapeutic agent.
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