Residue-Selective Inhibitors Discovery via Covalent DNA-Encoded Chemical Libraries with Diverse Warheads DOI
Xinyuan Wu, Jian Pan,

Rufeng Fan

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: April 28, 2025

Covalent small molecule drugs have emerged as a crucial support in precision therapy due to their high selectivity and robust potency. DNA-encoded chemical library (CoDEL) technology is an advanced platform for covalent drug discovery. However, the application of CoDELs constrained by single-residue focus limited warhead diversity. Here we report method identify residue-selective inhibitors using with diverse warheads targeting multiple distinct residues. We systematically evaluated reactivity 17 9 nucleophilic amino acids FGFR2 then constructed comprising 24.8 million compounds. These enabled identification active cysteine, lysine, arginine, or glutamic acid. The lysine-targeting inhibitor engaged novel reactive site. arginine-targeting demonstrated subtype overcame resistance. acid-targeting validated druggability this unconventional residue findings suggest that our work could potentially expand target space promote harnessing power CoDELs.

Language: Английский

DNA-Compatible N-Formylation of Amines by Using TMSCF2Br DOI
Huilin Liao, Xianfu Fang, Huihong Wang

et al.

The Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 15, 2025

DNA-encoded libraries (DELs) have emerged as powerful tools in drug discovery. Protected amino acids serve essential building blocks the construction of DELs, resulting widespread presence groups within these libraries. N-formylation free amines not only enhances activity lead compounds but also functions an effective amino-protecting strategy. In this study, we introduce trimethyl(bromodifluoromethyl)silane (TMSCF2Br) a novel reagent for DEL synthesis. This approach demonstrates robustness DEL-compatible synthesis and enables library diversification through functional group transformation (FGT). Additionally, achieved efficient removal formyl groups, enabling to be strategically used on-DNA protection orthogonal Fmoc Boc groups.

Language: Английский

Citations

0
Residue-Selective Inhibitors Discovery via Covalent DNA-Encoded Chemical Libraries with Diverse Warheads DOI
Xinyuan Wu, Jian Pan,

Rufeng Fan

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: April 28, 2025

Covalent small molecule drugs have emerged as a crucial support in precision therapy due to their high selectivity and robust potency. DNA-encoded chemical library (CoDEL) technology is an advanced platform for covalent drug discovery. However, the application of CoDELs constrained by single-residue focus limited warhead diversity. Here we report method identify residue-selective inhibitors using with diverse warheads targeting multiple distinct residues. We systematically evaluated reactivity 17 9 nucleophilic amino acids FGFR2 then constructed comprising 24.8 million compounds. These enabled identification active cysteine, lysine, arginine, or glutamic acid. The lysine-targeting inhibitor engaged novel reactive site. arginine-targeting demonstrated subtype overcame resistance. acid-targeting validated druggability this unconventional residue findings suggest that our work could potentially expand target space promote harnessing power CoDELs.

Language: Английский

Citations

0