Structure-Based Design and Optimization of Novel PHGDH Inhibitors for Overcoming Erlotinib-Resistant Lung Cancer

  • J Med Chem. 2026 Jun 25;69(12):14390-14413. doi: 10.1021/acs.jmedchem.6c00144.
Xingmei Wu  1 ,  Shuai Tang  2  3 ,  Yiyang Yan  2 ,  Xinyu Cao  1 ,  Yixin Cen  1 ,  Xiaojing Lan  2 ,  Yingjie Zhu  2 ,  Da-Yu Shi  1 ,  Guo-Qiang Lin  1 ,  Ping Tian  1 ,  Min Huang  2  3 ,  Dingding Gao  1
Affiliations
  • 1. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201203, China.
  • 3. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
PMID: 42263187 DOI: 10.1021/acs.jmedchem.6c00144
Abstract

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 IC50 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.

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