Identification of benzo[<i> b</i> ]thiophene-1,1-dioxide derivatives as novel PHGDH covalent inhibitors
发布时间：2025-11
点击次数：
- 发布时间：
- 2025-11
- 影响因子：
- 4.7
- DOI码：
- 10.1016/j.bioorg.2024.107330
- 论文名称：
- Identification of benzo[<i> b</i> ]thiophene-1,1-dioxide derivatives as novel PHGDH covalent inhibitors
- 发表刊物：
- BIOORGANIC CHEMISTRY
- 摘要：
- The increased de novo serine biosynthesis confers many advantages for tumorigenesis and metastasis. Phosphoglycerate dehydrogenase (PHGDH), a rate -limiting enzyme in serine biogenesis, exhibits hyperactivity across multiple tumors and emerges as a promising target for cancer treatment. Through screening our in-house compound library, we identified compound Stattic as a potent PHGDH inhibitor (IC 50 = 1.98 +/- 0.66 mu M). Subsequent exploration in structural activity relationships led to the discovery of compound B12 that demonstrated the increased enzymatic inhibitory activity (IC 50 = 0.29 +/- 0.02 mu M). Furthermore, B12 exhibited robust inhibitory effects on the proliferation of MDA-MB-468, NCI -H1975, HT1080 and PC9 cells that overexpress PHGDH. Additionally, using a [U - 13 C 6 ] -glucose tracing assay, B12 was found to reduce the production of glucose -derived serine in MDA-MB-468 cells. Finally, mass spectrometry -based peptide profiling, mutagenesis experiment and molecular docking study collectively suggested that B12 formed a covalent bond with Cys421 of PHGDH.
- 第一作者：
- caoxinyu
- 论文类型：
- 期刊论文
- 通讯作者：
- 田平,tangshuai,gaodingding
- 卷号：
- 146
- ISSN号：
- 0045-2068
- 是否译文：
- 否
- 发表时间：
- 2024-05
- 他引次数：
- 3