发布时间：

2025-11

影响因子：

6.9

DOI码：

10.1021/acs.jmedchem.2c01202

论文名称：

Discovery of Novel Drug-like PHGDH Inhibitors to Disrupt Serine Biosynthesis for Cancer Therapy

发表刊物：

JOURNAL OF MEDICINAL CHEMISTRY

摘要：

Being the rate-limiting enzyme within the serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH) is abnormally overexpressed in numerous malignant tumor cells and is a promising target for cancer treatment. Here, we report a series of novel PHGDH inhibitors using a focused compound screening and structural optimization approach. The lead compound D8 displayed good enzymatic inhibitory activity (IC50 = 2.8 +/- 0.1 mu M), high binding affinity (Kd = 2.33 mu M), and sensitivity to the cell lines with the PHGDH gene amplification or overexpression. Furthermore, D8 was proven to restrict the de novo serine synthesis from glucose within MDA-MB-468 cells. X-ray crystallographic analysis, molecular dynamics simulations, and mutagenesis experiments on PHGDH revealed the binding site at D175 inside the NAD+-binding pocket. Finally, D8 exhibited excellent in vivo pharmacokinetic properties (F = 82.0%) and exerted evident antitumor efficacy in the PC9 xenograft mouse model.

第一作者：

gaodingding,tangshuai,cenyixin

论文类型：

期刊论文

通讯作者：

liqinghua,黄敏,田平

卷号：

66

期号：

1

页面范围：

285-305

ISSN号：

0022-2623

是否译文：

否

发表时间：

2023-01

他引次数：

9