Application of encoded library technology (ELT) to a protein–protein interaction target: Discovery of a potent class of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists

Kollmann, Christopher; Bai, Xiaopeng; Tsai, Chih-Hsuan; Yang, Hongfang; Lind, Kenneth; Skinner, Steven R.; Zhu, Zhengrong; Israel, David I.; Cuozzo, John W.; Morgan, Barry A.; Yuki, Koichi; Xie, Can; Springer, Timothy A.; Shimaoka, Motomu; Evindar, Ghotas

doi:10.1016/j.bmc.2014.01.050

Cited by 87 publications

(72 citation statements)

References 31 publications

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“…Historically, we examined an individual library through cube analysis to provide guidance for off-DNA hit to lead efforts30313233353751. Figure 3 shows a representative data set for a single target, DHFR, where chemical clusters are plotted with their average molecular weight versus the average cLogP.…”

Section: Discussionmentioning

confidence: 99%

“…The technology has become widely used throughout the pharmaceutical, biotech and academic environments to discover ligands and is continually evolving252627. ELT has been employed successfully to identify numerous molecules that bind to proteins from diverse target classes and sample deep chemical space as well as understand structure activity relationships directly from the screening output2829303132333435363738.…”

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confidence: 99%

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Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

et al. 2017

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The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis. Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

et al. 2017

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“…1−5 Examples include the discovery of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists, 6 ADAMTS-5, 7 and RIP3 Kinase 8 inhibitors. The DNA moiety of the conjugate functions as a barcode, encoding the structure of the small molecule to which it is attached.…”

Section: ■ Introductionmentioning

confidence: 99%

DNA Compatible Multistep Synthesis and Applications to DNA Encoded Libraries

et al. 2015

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Complex mixtures of DNA encoded small molecules may be readily interrogated via high-throughput sequencing. These DNA encoded libraries (DELs) are commonly used to discover molecules that interact with pharmaceutically relevant proteins. The chemical diversity displayed by the library is key to successful discovery of potent, novel, and drug-like chemical matter. The small molecule moieties of DELs are generally synthesized though a multistep process, and each chemical step is accomplished while it is simultaneously attached to an encoding DNA oligomer. Hence, library chemical diversity is often limited to DNA compatible synthetic reactions. Herein, protocols for 24 reactions are provided that have been optimized for high-throughput production of DELs. These protocols detail the multistep synthesis of benzimidazoles, imidazolidinones, quinazolinones, isoindolinones, thiazoles, and imidazopyridines. Additionally, protocols are provided for a diverse range of useful chemical reactions including BOC deprotection (under pH neutral conditions), carbamylation, and Sonogashira coupling. Last, step-by-step protocols for synthesizing functionalized DELs from trichloronitropyrimidine and trichloropyrimidine scaffolds are detailed.

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“…33–42 In contrast to DCLs, due to DNA's high encoding capacity, DELs can contain millions of different compounds; 43–46 library selection can be feasibly decoded using PCR amplification and DNA sequencing. 47,48 Therefore, introducing DNA-encoding to DCLs could be an effective strategy to address the limitation of their library size.…”

Section: Introductionmentioning

confidence: 99%