Novel oxadiazole analogs as anticancer agents: Design, synthesis, in vitro and in vivo biological evaluation, and computer studies of sphingosine kinase inhibitors

IF 3.5 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2026-02-01 Epub Date: 2025-11-14 DOI:10.1016/j.bmc.2025.118487

Fuxun Huang , Xinmei Yang , Haiyang Wang , Xiujuan Shi , Xiaodong Zhao , Junru Liu , Yueyang Sun , Xingbo Song , Tong Li , Zhaoyang Li , Xi Qiu , Jingtong Feng , Yuanyuan Liu , Yuqi Gao , Yanling Mu , Zhengguo Cui , Peng Zhan , Bo Liu

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引用次数: 0

Abstract

Sphingosine kinases (SphKs) have emerged as novel therapeutic targets for treating cancer and inflammation via the SphK/S1P signaling pathway. However, the development of selective SphK inhibitors has been challenging because of their limited specificity. In this study, we used pharmacophore- and docking-based virtual screening to identify the lead compound DTD-8 (SphK1 IC₅₀ = 79 ± 0.73 μM) and then optimized the structure through structure-based drug design. Our newly synthesized 1,2,4-oxadiazole derivative, compound 22c, demonstrated selective inhibition against SphK2 (IC₅₀ = 2.24 ± 0.60 μM) over SphK1 (IC₅₀ = 64.20 ± 1.53 μM), representing 28-fold selectivity for SphK2. It also exhibited more potent anticancer activity against DU145 cells (IC₅₀ = 3.09 ± 0.67 μM) than cisplatin (IC₅₀ = 10.67 ± 1.00 μM) owing to its ability to induce S/G2 phase arrest and apoptosis.

In rats, Compound 22c showed favorable pharmacokinetic properties, including good metabolic stability (T₁_/₂ = 19.6 h) and high plasma exposure (AUC₀–t = 1077.40 ng h/mL), along with promising in vivo tumor growth inhibition (TGI = 65.96 %). Given its moderate oral bioavailability (F = 54.88 %) and potent anticancer effects, 22c requires further investigation. These findings provide valuable insights for developing novel SphK2-targeted anticancer agents.

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新型恶二唑类抗癌药物：鞘氨醇激酶抑制剂的设计、合成、体外和体内生物学评价及计算机研究

sphingosin激酶（SphKs）已成为通过SphK/S1P信号通路治疗癌症和炎症的新靶点。然而，选择性SphK抑制剂的开发一直具有挑战性，因为它们的特异性有限。在本研究中，我们使用基于药效团和对接的虚拟筛选方法鉴定了先导化合物DTD-8 (SphK1 IC₅₀= 79±0.73 μM)，然后通过基于结构的药物设计对结构进行优化。我们新合成的1,2,4-二唑衍生物，化合物22c，对SphK2 （IC₅₀= 2.24±0.60 μM）的选择性抑制作用优于SphK1 (IC₅₀= 64.20±1.53 μM)，对SphK2的选择性为28倍。由于其诱导S/G2期阻滞和细胞凋亡的能力，它对DU145细胞（IC₅₀= 3.09±0.67 μM）的抗癌活性也比顺铂（IC₅₀= 10.67±1.00 μM）更强。在大鼠中，化合物22c表现出良好的药代动力学特性，包括良好的代谢稳定性（T₁/ 2 = 19.6 h）和高血浆暴露（AUC 0 -t = 1077.40 ng h/mL），以及有希望的体内肿瘤生长抑制（TGI = 65.96%）。鉴于其中等的口服生物利用度（F = 54.88%）和有效的抗癌作用，22c需要进一步的研究。这些发现为开发新的sphk2靶向抗癌药物提供了有价值的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.