Discovery of indole-2-one derivatives as BRD4 (BD1) selective inhibitors
Xue-Peng Qiao1, Xue-Ting Wang1, Shuai Wang1
1School of Pharmacy & Collaborative Innovation Center for Northwestern Chinese Medicine, Lanzhou University, Lanzhou 730000, China.
Abstract:
Bromodomain protein 4 (BRD4) is a member of the BET family, and its overexpression is closely associated with the development of many tumors. Inhibition of BRD4 shows great therapeutic potential in anti-tumor, and pan-BRD4 inhibitors show adverse effects of dose limiting toxicity and thrombocytopenia in clinical trials. To improve clinical effects and reduce side effects, more efforts have focused on seeking selective inhibitors of BD1 or BD2. Herein, a series of indole-2-one derivatives were designed and synthesized through docking-guided optimization to find BRD4-BD1 selective inhibitors, and their BRD4 inhibitory and antiproliferation activities were evaluated. Among them, compound 21r had potent BRD4 inhibitory activity (the IC50 values of 41 nM and 313 nM in BD1 and BD2 domain), excellent anti-proliferation (the IC50 values of 4.64 ± 0.30 µM, 0.78 ± 0.03 µM, 5.57 ± 1.03 µM against HL-60, MV-4-11 and HT-29 cells), and displayed low toxicity against normal cell GES-1 cells. Further studies revealed that 21r inhibited proliferation by decreasing the expression of proto-oncogene c-Myc, blocking cell cycle in G0/G1 phase, and inducing apoptosis in MV-4-11 cells in a dose-dependent manner. All the results showed that compound 21r was a potent BRD4 inhibitor with BD1 selectivity, which had potential in treatment of leukemia.
Insights
Researchers developed novel indole-2-one derivatives as selective inhibitors for Bromodomain protein 4 (BRD4) BD1. Compound 21r shows potent anti-tumor activity with low toxicity, offering potential for leukemia treatment.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Bromodomain protein 4 (BRD4) is implicated in tumor development.
- Existing pan-BRD4 inhibitors cause dose-limiting toxicities and thrombocytopenia.
- Selective inhibition of BRD4 domains (BD1 or BD2) is a therapeutic goal.
Purpose of the Study:
- To design and synthesize novel indole-2-one derivatives as selective BRD4-BD1 inhibitors.
- To evaluate the anti-tumor and anti-proliferation activities of these compounds.
- To identify a potent and selective BRD4-BD1 inhibitor with reduced toxicity.
Main Methods:
- Docking-guided optimization for drug design.
- Synthesis of indole-2-one derivatives.
- In vitro evaluation of BRD4 inhibitory and anti-proliferation activities.
- Assessment of toxicity against normal cells.
- Mechanistic studies involving c-Myc expression, cell cycle, and apoptosis.
Main Results:
- Compound 21r demonstrated potent BRD4 inhibitory activity, with higher potency against the BD1 domain (IC50 = 41 nM) compared to BD2 (IC50 = 313 nM).
- Compound 21r exhibited significant anti-proliferation effects against leukemia (HL-60, MV-4-11) and colon cancer (HT-29) cell lines (IC50s ranging from 0.78 to 5.57 µM).
- Low toxicity was observed against normal GES-1 cells, and compound 21r induced apoptosis and cell cycle arrest in MV-4-11 cells by downregulating c-Myc expression.
Conclusions:
- Compound 21r is a potent and selective BRD4-BD1 inhibitor.
- Compound 21r possesses significant anti-cancer properties and low toxicity.
- Compound 21r shows therapeutic potential for treating leukemia and other cancers driven by BRD4.
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