Structure-BasedDesign and Optimization of Novel PHGDHInhibitors for Overcoming Erlotinib-Resistant Lung Cancer

作者：Xingmei Wu (571884), Shuai Tang (325963), Yiyang Yan, Xinyu Cao (2508337), Yixin Cen, Xiaojing Lan, Yingjie Zhu (240610), Da-Yu Shi, Guo‐Qiang Lin, Ping Tian, Min Huang (161268), Dingding Gao · 发表于：Figshare · 年份：2026 · DOI：10.1021/acs.jmedchem.6c00144.s001 · 研究领域：Cancer, Hypoxia, and Metabolism、Peptidase Inhibition and Analysis、Amino Acid Enzymes and Metabolism

Phosphoglycerate dehydrogenase (PHGDH), a key regulator in the serine biosynthesis pathway, is aberrantly expressed in various cancers, making it an attractive therapeutic target. In this study, we designed and synthesized a series of PHGDH inhibitors using a structure-based approach. Among these, compounds 43 ( GDD-260) and 47 ( GDD-261 ) exhibited superior enzymatic inhibition with IC 50 values of 0.091 ± 0.013 μM and 0.061 ± 0.004 μM, respectively. Both compounds effectively suppressed de novo serine biosynthesis and showed antitumor activity in PHGDH-overexpressing MDA-MB-468 and PC9 cells. Notably, compounds 43 and 47 also demonstrated antiproliferative effects against erlotinib-resistant PC9 and HCC827 cell lines, exhibiting synergistic effects when combined with erlotinib. Compound 47 showed enhanced antitumor efficacy in erlotinib-resistant PC9 xenograft models in combination with erlotinib. The X-ray crystallographic analysis revealed the binding mode of 43 within the PHGDH active site. These findings provide a foundation for developing PHGDH-targeted anticancer therapies.