2. Academic Validation
  3. Discovery, SAR Study of GST Inhibitors from a Novel Quinazolin-4(1 H)-one Focused DNA-Encoded Library

Discovery, SAR Study of GST Inhibitors from a Novel Quinazolin-4(1 H)-one Focused DNA-Encoded Library

  • J Med Chem. 2023 Aug 24;66(16):11118-11132. doi: 10.1021/acs.jmedchem.2c02129.
Xin Wen 1 2,  Minmin Zhang 1 2,  Zhiqiang Duan 1,  Yanrui Suo 1 2,  Weiwei Lu 1,  Rui Jin 1,  Baiyang Mu 1,  Kaige Li 1,  Xu Zhang 1 2,  Linghua Meng 1 2,  Yu Hong 1 2,  Xingyu Wang 1 2,  Hangchen Hu 1,  Jian Zhu 3,  Weixiao Song 3,  Aijun Shen 1 2 4,  Xiaojie Lu 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai 201203, P. R. China.
  • 2 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3 Protein Crystallography Platform, WuXi AppTec (Suzhou) Co., Ltd., 1318 Wuzhong Avenue, Wuzhong District, Suzhou 215104, China.
  • 4 Lingang Laboratory, Shanghai 200031, China.
PMID: 37552553 DOI: 10.1021/acs.jmedchem.2c02129
Abstract

The DNA-encoded library (DEL) is a powerful hit-generation tool in drug discovery. This study describes a new DEL with a privileged scaffold quinazolin-4(3H)-one developed by a robust DNA-compatible multicomponent reaction and a series of novel glutathione S-transferase (GST) inhibitors that were identified through affinity-mediated DEL selection. A novel inhibitor 16 was subsequently verified with an inhibitory potency value of 1.55 ± 0.02 μM against SjGST and 2.02 ± 0.20 μM against hGSTM2. Further optimization was carried out via various structure-activity relationship studies. And especially, the co-crystal structure of the compound 16 with the SjGST was unveiled, which clearly demonstrated its binding mode was quite different from the known GSH-like compounds. This new type of probe is likely to play a different role compared with the GSH, which may provide new opportunities to discover more potent GST inhibitors.

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