Details

Autor(en) / Beteiligte

• Xia, Bing
• Franklin, G. Joseph
• Lu, Xiaojie
• Bedard, Katie L
• Grady, LaShadric C
• Summerfield, Jennifer D
• Shi, Eric X
• King, Bryan W
• Lind, Kenneth E
• Chiu, Cynthia
• Watts, Eleanor
• Bodmer, Vera
• Bai, Xiaopeng
• Marcaurelle, Lisa A

Titel

DNA-Encoded Library Hit Confirmation: Bridging the Gap Between On-DNA and Off-DNA Chemistry

Ist Teil von

• ACS medicinal chemistry letters, 2021-07, Vol.12 (7), p.1166-1172

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• DNA-encoded library (DEL) technology is a powerful platform for hit identification in academia and the pharmaceutical industry. When conducting off-DNA resynthesis hit confirmation after affinity selection, PCR/sequencing, and data analysis, one typically assumes a “one-to-one” relationship between the DNA tag and the chemical structure of the attached small-molecule it encodes. Because library synthesis often yields a mixture, this approximation increases the risk of overlooking positive discoveries and valuable information. To address this issue, we apply a library synthesis “recipe” strategy for on-DNA resynthesis using a cleavable linker, followed by direct affinity selection mass spectrometry (AS-MS) evaluation and identification of binder(s) from the released small-molecule mixture. We validate and showcase this approach employing the receptor-interacting-protein kinase 2 (RIP2) DEL campaign. We also designed and developed two cleavable linkers to enable this method, a photocleavable linker (nitrophenyl-based) and acid-labile linker (tetrahydropyranyl ether). The strategy provides an effective means of hit identification and rapid determination of key active component(s) of the mixture.