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
  • 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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