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Updated: Jun 11, 2026

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
Published on: June 26, 2019
Structure-Based Design and Optimization of Novel PHGDH Inhibitors for Overcoming Erlotinib-Resistant Lung Cancer
Xingmei Wu1, Shuai Tang2,3, Yiyang Yan2
1State 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.
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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