Ahmed M Almehdi, Samar Damiati, Ihsan A Shehadi, Mohamed El-Sadek, Arwyn T Jones, Abdalla El-Kabalawy, Yasmina Lashine, Yogendra Nayak, Sameh S M Soliman, Andrew D Westwell, Rania Hamdy
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引用次数: 0
Abstract
The Bcl-2 protein family plays a critical role in regulating apoptosis, making it a key target for cancer therapy. In this study, a series of novel Bcl-2 inhibitors have been designed, synthesized, and evaluated. To disrupt the interactions between anti-apoptotic Bcl-2 and pro-apoptotic proteins, compounds were developed based on essential pharmacophoric features. Among the tested compounds, R4, R14, R17, and R23 demonstrated potent anticancer activity with sub-micromolar IC50 concentrations across various Bcl-2 expressing human cancer cell lines (IC50 ranges: 1.46-7.67 µM for cancer cells). ELISA binding assays further validated the efficacy of R4, R14, and R23, showcasing their potency with IC50 values ranging from 0.25 to 0.63 µM, compared to gossypol and ABT-199 (venetoclax), with IC50 values of 0.6 and 0.038 µM, respectively. Furthermore, the R23 revealed a significant induction of late and early apoptosis and cell cycle arrest at G1 phase. Noteworthy, R23 emerged as a promising candidate with unique computational analysis, showing superior displacement of hydration sites and higher ΔG values in WaterMap studies. Moreover, molecular dynamics simulations reveal low root mean square deviation fluctuations, indicating strong and stable interactions with Bcl-2. These findings underscore the therapeutic potential of R23 as a Bcl-2 inhibitor.
期刊介绍:
Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies.
ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs.
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