DNA编码分子库Design and Synthesis of Biaryl DNA-Encoded Libraries.pdfVIP

Letter /acscombsci Design and Synthesis of Biaryl DNA-Encoded Libraries Yun Ding, * G. Joseph Franklin, Jennifer L. DeLorey,† Paolo A. Centrella,‡ Sibongile Mataruse,§ Matthew A. Clark,‡ Steven R. Skinner, and Svetlana Belyanskaya GlaxoSmithKline, Platform Technology Science, ELT-Boston, 830 Winter Street, Waltham, Massachusetts 02451, United States S *Supporting Information ABSTRACT: DNA-encoded library technology (ELT) is a powerful tool for the discovery of new small-molecule ligands to various protein targets. Here we report the design and synthesis of biaryl DNA-encoded libraries based on the scaffold of 5-formyl 3-iodobenzoic acid. Three reactions on DNA template, acylation, Suzuki−Miyaura coupling and reductive amination, were applied in the library synthesis. The three cycle library of 3.5 million diversity has delivered potent hits for phosphoinositide 3- kinase α (PI3Kα). KEYWORDS: Suzuki−Miyaura cross-coupling, DNA-encoded library technology he DNA-encoded library (DEL) technology has been Scheme 1 Tdeveloped over decades and now is widely used both in the pharmaceutical industry and in academia.1−4 DNA encoding allows simultaneous interrogation of millions to billions of small molecules through affinity selection. Using high-throughput sequencing technologies,5 the output sequen- ces can be amplified and characterized to yield the structures of potential hits. As reported earlier,6−10 we and others have discovered potent inhibitors for various targ