Discovery of a Covalent Inhibitor Targeting the PHGDH Dimer Interface with Antitumor Efficacy

  • J Med Chem. 2026 Jun 25;69(12):14530-14554. doi: 10.1021/acs.jmedchem.6c00456.
Lei Feng  1  2 ,  Yang Liu  3  4 ,  Yiwei Zhang  2  5 ,  Zhongjiao Fan  1 ,  Xinyuan Wu  2  5 ,  Xiancheng Yang  1 ,  Leyi Liu  1 ,  Zhibei Qu  1 ,  Ying Shen  3  4 ,  Xiaojie Lu  2  5 ,  Lu Zhou  1
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3. Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 4. Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education & Shanghai, Shanghai 200025, China.
  • 5. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
PMID: 42284116 DOI: 10.1021/acs.jmedchem.6c00456
Abstract

Protein oligomerization is functionally essential for many Enzymes, yet small-molecule strategies that directly target dimer interfaces remain challenging. Cysteine residues at protein dimer interfaces offer chemically addressable sites for modulating oligomeric assembly. Here, we used covalent DNA-encoded chemical library (CoDEL) screening to identify site-selective covalent hits targeting the PHGDH dimer interface. Covalent hits emerging from CoDEL screening were optimized to yield a selective covalent inhibitor engaging the interfacial Cys281. A representative compound, D5-2, potently disrupts PHGDH dimerization and inhibits its enzymatic activity, restores sensitivity to EGFR tyrosine kinase inhibitors in resistant lung adenocarcinoma cells in vitro, and exhibits antitumor efficacy in mouse xenograft models. Together, these findings establish dimer-interface cysteine targeting as a mechanism-based and therapeutically relevant strategy for modulating PHGDH function, and highlight the potential of CoDEL for discovering covalent inhibitors of protein-protein interfaces.

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