Discovery of W478, a novel SHMT2 inhibitor for the treatment of esophageal carcinoma

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-09-23 DOI:10.1016/j.bioorg.2025.109028

Hafiz Muhammad Bilal Akram , Yulin Liu , Jianshu Dong , Xueke Zhao , Lidong Wang , Wen Zhao , Hongmin Liu , Liying Ma , Cong Han

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Abstract

Esophageal cancer has been regarded as a serious malignancy due to its poor prognosis and high mortality rate. Serine hydroxymethyltransferase 2 (SHMT2) is emerging as an attractive target for esophageal cancer therapy. Compound W478 was identified as a potent SHMT2 inhibitor with an IC₅₀ value of 1.21 μM, especially whose chemical structure is distinct from the reported SHMT2 inhibitors. Both cellular thermal shift assay and isothermal titration calorimetry experiments showed that compound W478 tightly bound to SHMT2 (K_D = 10.6 ± 1.2 μM). The molecular docking analysis revealed its binding at the folate binding site of SHMT2. Moreover, compound W478 exhibited a significant antiproliferative effect on human esophageal cancer cell lines, KYSE-450 and KYSE-70 cells (IC₅₀ = 1.62 μM, 1.18 μM, respectively). The wound healing and transwell assays showed that compound W478 could inhibit the migratory and invasive potential of KYSE-450 and KYSE-70 cells in a dose-dependent manner. Further studies demonstrated that compound W478 could induce cell arrest at the G2/M phase and promote cell apoptosis and ROS production in KYSE-450 and KYSE-70 cells. These findings indicated that compound W478 could serve as a promising lead compound for the development of SHMT2 inhibitor to address esophageal carcinoma.

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新型SHMT2抑制剂W478的发现治疗食管癌

食管癌因其预后差、死亡率高而被认为是一种严重的恶性肿瘤。丝氨酸羟甲基转移酶2 （SHMT2）正在成为食管癌治疗的一个有吸引力的靶点。化合物W478是一种有效的SHMT2抑制剂，IC50值为1.21 μM，其化学结构与已有报道的SHMT2抑制剂不同。细胞热移实验和等温滴定量热实验表明，化合物W478与SHMT2紧密结合（KD = 10.6±1.2 μM）。分子对接分析显示其与SHMT2的叶酸结合位点结合。此外，化合物W478对人食管癌细胞系KYSE-450和KYSE-70细胞具有显著的抗增殖作用（IC50分别为1.62 μM、1.18 μM）。伤口愈合和transwell实验表明，化合物W478可以抑制KYSE-450和KYSE-70细胞的迁移和侵袭潜力，并呈剂量依赖性。进一步的研究表明，化合物W478可以诱导KYSE-450和KYSE-70细胞在G2/M期细胞停滞，促进细胞凋亡和ROS的产生。这些结果表明，化合物W478可以作为开发治疗食管癌的SHMT2抑制剂的先导化合物。

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 Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.