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Design, synthesis, and antitumor evaluation of triazolopyridine derivatives as novel inhibitors for BRD4
Jing-Ying Liu1, Hong-En Zhang1, Cheng Wang1
1Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, PR China.
Abstract:
The bromodomain-containing protein 4 (BRD4) is an epigenetic regulatory 'reader' belonging to the bromodomain and extra-terminal domain (BET) family. Several studies have demonstrated that the high expression of BRD4 is closely related to the occurrence and development of various cancers, so BRD4 has become a promising target for cancer treatment. However, there are no drugs targeting BRD4 available on the market, the development of novel BRD4 inhibitors is of great significance. This paper describes a series of triazolopyridine derivatives exhibiting favorable BRD4 inhibitory activity, which have not been reported before. Among them, the representative compound 12m showed potent BRD4 BD1 inhibitory activity, of which the inhibition rate is better than the other compounds. In MV4-11 cell line, compound 12m also showed excellent anti-cancer activity (IC50 = 0.02 μM), which is superior to (+)-JQ1 (IC50 = 0.03 μM). Through molecular docking, it was discovered that compound 12m could combine with the acetyl-lysine binding site of BRD4 BD1 and form a hydrogen bond with a crucial amino acid residue Asn140. Additionally, compound 12m was found to have good metabolic stability with a clearance rate of only 0.3 μL/min/nm in mouse liver microsomes. Apoptosis experiments demonstrated that compound 12m induced apoptosis better than (+)-JQ1 at the same concentration, and the apoptosis rate of compound 12m increased from 43.2 % to 83.2 %. Subsequent in vivo pharmacokinetic testing of compound 12m in ICR mice yielded a good oral absorption and utilization of compound 12m (F = 44.8 %). The results indicate that triazolopyridine is an outstanding skeleton for developing novel BRD4 inhibitors, and compound 12m is a promising lead compound for further optimization and extensive clinical development.
Insights
Researchers developed novel triazolopyridine derivatives as potent bromodomain-containing protein 4 (BRD4) inhibitors for cancer therapy. Compound 12m demonstrated significant anti-cancer activity and good metabolic stability, showing promise for clinical development.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Epigenetics
Background:
- Bromodomain-containing protein 4 (BRD4) is a key epigenetic regulator implicated in various cancers.
- High BRD4 expression correlates with cancer occurrence and progression, making it a significant therapeutic target.
- Currently, no drugs targeting BRD4 are available, highlighting the need for novel inhibitors.
Purpose of the Study:
- To design and synthesize novel triazolopyridine derivatives with BRD4 inhibitory activity.
- To evaluate the anti-cancer efficacy and mechanism of action of these novel compounds.
- To assess the pharmacokinetic properties and metabolic stability of promising lead compounds.
Main Methods:
- Synthesis of a series of triazolopyridine derivatives.
- In vitro assays to determine BRD4 inhibitory activity and anti-cancer effects in MV4-11 cell lines.
- Molecular docking to elucidate the binding interaction with BRD4 BD1.
- In vitro metabolic stability assessment using mouse liver microsomes.
- Apoptosis assays and in vivo pharmacokinetic studies in mice.
Main Results:
- Novel triazolopyridine derivatives exhibiting significant BRD4 inhibitory activity were synthesized.
- Compound 12m demonstrated potent BRD4 BD1 inhibition and superior anti-cancer activity (IC50 = 0.02 μM) compared to (+)-JQ1 in MV4-11 cells.
- Molecular docking revealed compound 12m binds to the acetyl-lysine site of BRD4 BD1, forming a hydrogen bond with Asn140.
- Compound 12m exhibited good metabolic stability (clearance = 0.3 μL/min/nm) and induced significant apoptosis (83.2%).
- In vivo studies showed good oral bioavailability for compound 12m (F = 44.8%).
Conclusions:
- Triazolopyridine serves as a promising scaffold for developing novel BRD4 inhibitors.
- Compound 12m is identified as a potent lead compound with significant anti-cancer potential.
- Further optimization and clinical development of compound 12m are warranted for cancer therapy.
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