Xin Wen; Minmin Zhang; Zhiqiang Duan; Yanrui Suo; Weiwei Lu; Rui Jin; Baiyang Mu; Kaige Li; Xu Zhang; Linghua Meng; Yu Hong; Xingyu Wang; Hangchen Hu; Jian Zhu; Weixiao Song; Aijun Shen; Xiaojie Lu
J. Med. Chem., 2023, 66(16), 11118-11132
https://doi.org/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.