Biocatalytic- and Chemoproteomic-Guided Discovery of a PHGDH Inhibitor from Chemoenzymatic-Promoted DNA-Encoded Libraries Selection Platform

  • J Am Chem Soc. 2025 Dec 3;147(48):44396-44405. doi: 10.1021/jacs.5c14634.
Yiwei Zhang  1  2 ,  Yuqiu Lan  1  2 ,  Rufeng Fan  1  2 ,  Lei Feng  3 ,  Guoliang Wang  4 ,  Xinyuan Wu  1 ,  Lulu Wen  5 ,  Zhiqiang Duan  1 ,  Yueyue Xia  4 ,  Xudong Wang  1  2 ,  Lingrui Zhang  4 ,  Lu Zhou  3 ,  Minjia Tan  1  2 ,  Cangsong Liao  6  2 ,  Xiaojie Lu  1  2  3  5  4
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3. School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 5. Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
  • 6. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
PMID: 41266292 DOI: 10.1021/jacs.5c14634
Abstract

DNA-encoded libraries (DELs) have emerged as an effective and efficient selection strategy for lead compound discovery in academia and industry over the past few decades. Despite recent advancements in this field, DEL remains limited by sensitive DNA-based constructs, particularly with low selection success rates resulting from the random selection of targets. Here, we describe a chemoenzymatic on-DNA reaction for DEL syntheses and develop a chemoproteomic-guided DEL selection platform. This platform, termed FF tags-biocatDEL, integrates DEL technology, chemoenzymatic synthesis, and fully functionalized (FF) chemical tags to match DELs with selection targets, even with limited information about ligandable hotspots. Using two diazirine-based FF indole probes, we comprehensively surveyed binding partners in cells and identified phosphoglycerate dehydrogenase (PHGDH) as a potential target for DEL selection. DEL01 and DEL02 were designed, synthesized, and selected against PHGDH, leading to the identification of a novel enzyme-active compound with an IC50 value of 2.5 μM. Our strategy, utilizing FF tags-biocatDEL, establishes a generalizable workflow for rapid target hunting and ligand discovery. It provides an effective method for precisely matching DELs with potential targets, demonstrating its significant potential as a complementary approach to drug discovery based on DELs.

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