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

Abstract

The DNA-encoded library (DEL) is a powerful hitgeneration 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 cocrystal 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.

DNA-Encoded Library Technology─A Catalyst for Covalent Ligand Discovery

“…This platform enables the simultaneous interrogation of billions of molecules to discover novel binders in an affinity-mediated selection format. DEL is a well-established approach, with several hit identification examples reported. − As covalent small molecules have emerged as an active area of drug discovery interest, efforts to identify molecules with this desired mode of action are being undertaken. DEL technology enables the identification of covalent ligands with desired properties, such as selectivity, potency, and extended occupancy.…”

Discovery of Two Non-Udp-Mimic Inhibitors of O-Glcnac Transferase by Screening a Dna-Encoded Library

“…The technology uses the combinatorial synthesis method to build up large libraries [30]. Since 2002 the DEL technology is a tool in medicinal chemistry for screening purposes where identification of hits is facilitated by the DNA tag [31][32][33][34][35][36][37]. Here we report on the discovery of new non-UDP mimetic OGT inhibitors by using the DELopen platform, a DEL available to academic users by WuXi AppTec.…”