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

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.