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Discovery of Novel Inhibitors of BRD4 for Treating Prostate Cancer: A Comprehensive Case Study for Considering Water
Haiyang Zhong1, Xinyue Wang1, Shicheng Chen1
1College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Abstract:
Androgen receptor (AR) is the primary target for treating prostate cancer (PCa), which inevitably progresses due to drug-resistant mutations. Bromodomain-containing protein 4 (BRD4) has been a new potential drug target for PCa treatment. Herein, we report the rational design and discovery of novel BRD4 inhibitors through computer-aided drug design (CADD), and a hit compound SQ-1 (IC50 = 676 nM) was identified by structure-based virtual screening (SBVS) with the conserved water network. To optimize the structure of SQ-1, the free energy landscape was constructed, and the binding mechanism was explored by characterizing the water profile and the dissociation mechanism. Finally, the compound SQ-17 with improved inhibitory activity (IC50 < 100 nM) was discovered, which showed potent antiproliferative activity against LNCaP. These data highlighted a successful attempt to identify and optimize a small molecule by comprehensive CADD application and provided essential clues for developing novel therapeutics for PCa treatment.
Insights
Researchers discovered novel drug candidates targeting Bromodomain-containing protein 4 (BRD4) for prostate cancer (PCa) treatment. Computer-aided drug design led to compound SQ-17, showing potent activity against drug-resistant PCa cells.
Area of Science:
- Oncology
- Medicinal Chemistry
- Computational Biology
Background:
- Androgen receptor (AR) is a key target in prostate cancer (PCa), but resistance develops.
- Bromodomain-containing protein 4 (BRD4) presents a promising new therapeutic target for PCa.
Purpose of the Study:
- To rationally design and discover novel BRD4 inhibitors for PCa treatment using computer-aided drug design (CADD).
- To optimize initial hit compounds for improved efficacy against PCa.
Main Methods:
- Structure-based virtual screening (SBVS) utilizing conserved water networks to identify initial hit compounds.
- Free energy landscape construction and binding mechanism analysis to guide structure optimization.
- In vitro evaluation of antiproliferative activity against LNCaP cells.
Main Results:
- A hit compound, SQ-1, was identified with an IC50 of 676 nM.
- Optimization efforts led to the discovery of SQ-17 with improved inhibitory activity (IC50 < 100 nM).
- SQ-17 demonstrated potent antiproliferative effects on LNCaP cells.
Conclusions:
- Comprehensive CADD successfully identified and optimized a novel BRD4 inhibitor for PCa.
- The findings provide a foundation for developing new therapeutics against drug-resistant prostate cancer.
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