3-苯基-[1,2,4]三唑[4,3-a]吡啶衍生物作为结直肠癌有效平滑抑制剂的发现

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-04-27 DOI:10.1016/j.bmc.2025.118214

Fengqiu Guo , Yangcheng Ai , Yongxin Chen , Guowu Wu , Huanxian Wu , Jingyun lin , Ying Jiang , Jiajie Zhang , Tingting Zhang

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引用次数: 0

摘要

Hedgehog （Hh）信号通路的Smoothened （SMO）与结直肠癌（CRC）的发生有着复杂的关系，但SMO抑制剂Vismodegib缺乏治疗效果。基于保持临界相互作用和环取代的原则，设计并合成了一系列3-苯基-[1,2,4]三唑[4,3-a]吡啶衍生物。其中，化合物A11对SMOWT （IC50 = 0.27±0.06µM）和SMOD473H （IC50 = 0.84±0.12µM）分别表现出显著的抑制活性，对正常细胞的毒性可忽略不计。此外，与Vismodegib相比，A11对CRC细胞表现出更强的抗增殖活性。此外，A11竞争性地与SMO结合并抑制其下游信号通路。分子模拟研究表明，A11的三唑吡啶环可能参与了与SMO结合的重要相互作用。总之，这些结果表明A11作为一种SMO抑制剂治疗CRC值得进一步研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Discovery of 3-phenyl-[1,2,4]triazolo[4,3-a]pyridine derivatives as potent smoothened inhibitors against colorectal carcinoma

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Discovery of 3-phenyl-[1,2,4]triazolo[4,3-a]pyridine derivatives as potent smoothened inhibitors against colorectal carcinoma

Smoothened (SMO) in Hedgehog (Hh) signaling pathway is intricately associated with the genesis of colorectal carcinoma (CRC), but SMO inhibitor Vismodegib lacks of therapeutic benefits. Based on the principles of preserving critical interactions and ring substitution, a series of 3-phenyl-[1,2,4]triazolo[4,3-a]pyridine derivatives were designed and synthesized. Among them, compound A11 exhibited significant inhibitory activity against SMO^WT (IC₅₀ = 0.27 ± 0.06 µM) and SMO^D473H (IC₅₀ = 0.84 ± 0.12 µM), respectively, while displayed negligible toxicity towards normal cells. Furthermore, A11 demonstrated superior antiproliferative activity against CRC cells compared to Vismodegib. In additions, A11 competitively bound to SMO and inhibit its downstream signaling pathways. Molecular modeling studies suggested that the triazolopyridine ring of A11 may contribute to the important interaction for binding to SMO. In sum, these results suggest that A11 deserves further investigation as a SMO inhibitor for CRC treatment.

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.