Discovery of a Covalent Kinase Inhibitor from a DNA-Encoded Small-Molecule Library × Protein Library Selection

Chan, Alix I.; McGregor, Lynn M.; Jain, Tara; Liu, David R.

doi:10.1021/jacs.7b04880

Cited by 70 publications

(66 citation statements)

References 31 publications

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“…The results confirmed known small molecule:protein interactions and also revealed that ethacrynic acid is a novel ligand and inhibitor of MAP2K6 kinase. Ethacrynic acid inhibits MAP2K6, in part, through alkylation of a non-conserved cysteine residue (92).…”

Section: Dna-encoded Chemical Libraries For the Discovery Of Covalentmentioning

confidence: 99%

DNA-Encoded Chemical Libraries: A Selection System Based on Endowing Organic Compounds with Amplifiable Information

Neri

Lerner

2018

Annu. Rev. Biochem.

300

272

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The discovery of organic ligands that bind specifically to proteins is a central problem in chemistry, biology, and the biomedical sciences. The encoding of individual organic molecules with distinctive DNA tags, serving as amplifiable identification bar codes, allows the construction and screening of combinatorial libraries of unprecedented size, thus facilitating the discovery of ligands to many different protein targets. Fundamentally, one links powers of genetics and chemical synthesis. After the initial description of DNA-encoded chemical libraries in 1992, several experimental embodiments of the technology have been reduced to practice. This review provides a historical account of important milestones in the development of DNA-encoded chemical libraries, a survey of relevant ongoing research activities, and a glimpse into the future.

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Section: Dna-encoded Chemical Libraries For the Discovery Of Covalentmentioning

confidence: 99%

DNA-Encoded Chemical Libraries: A Selection System Based on Endowing Organic Compounds with Amplifiable Information

Neri

Lerner

2018

Annu. Rev. Biochem.

300

272

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“…[27] Over recent years DNA-encoded library sizes have continued to grow,w ith academic and pharmaceutical laboratories now reporting libraries with billions or even trillions of unique compounds. [28] Today,t he use of DNA-recorded chemistry in academia and industry has become commonplace and has resulted in lead compound identification for aw ide range of high-profile biomedical targets,i ncluding GPCRs, [29] kinases, [30] proteases, [31] and many others. [32] Figure 2.…”

Section: Dna-recorded Chemistrymentioning

confidence: 99%

Nucleic Acid‐Barcoding Technologies: Converting DNA Sequencing into a Broad‐Spectrum Molecular Counter

Liszczak

Muir

2019

Angew Chem Int Ed

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The emergence of high-throughput DNA sequencing technologies sparked an immediate revolution in the field of genomics that has rippled into many branches of the life and physical sciences. The remarkable sensitivity, specificity, throughput, and multiplexing capacity that are inherent to massively parallel DNA sequencing have since motivated its use as a broad-spectrum molecular counter in small molecule and peptide-based inhibitor discovery, high-throughput biochemistry, protein and cellular detection and diagnostics, and even materials science. A key aspect of extrapolating DNA sequencing to 'non-traditional' applications is the underlying need to append nucleic acid barcodes to entities of interest. In this review, we describe the chemical and biochemical approaches that have enabled facile nucleic acid barcoding of proteinaceous and non-proteinaceous materials, and provide exciting examples of downstream technologies that have been made possible by DNA-encoded molecules. Considering that commercially available high-throughput sequencers were first released less than 15 years ago, we believe related applications will continue to mature for years to come, and close by proposing potential new frontiers to support this assertion.

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“…Chemical and photoaffinity labeling of DNA-encoded compounds [23,24] and DNA aptamers [25] to target proteins were reported to identify unknown targets or screen novel binders. Furthermore, Liu et al reported a method called "interaction determination using unpurified proteins" to selectively amplify DNA sequences encoding the information of ligand-target pairs from a heterogenous mixture of DNA-encoded chemical library and proteins [26]. In their method, the target proteins were also tagged with short DNA that hybridized with DNA barcodes on the ligands.…”

Section: Introductionmentioning

confidence: 99%

Photocrosslinking of cDNA Display Molecules with Their Target Proteins as a New Strategy for Peptide Selection

2020

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Binding peptides for given target molecules are often selected in vitro during drug discovery and chemical biology research. Among several display technologies for this purpose, complementary DNA (cDNA) display (a covalent complex of a peptide and its encoding cDNA linked via a specially designed puromycin-conjugated DNA) is unique in terms of library size, chemical stability, and flexibility of modification. However, selection of cDNA display libraries often suffers from false positives derived from non-specific binding. Although rigorous washing is a straightforward solution, this also leads to the loss of specific binders with moderate affinity because the interaction is non-covalent. To address this issue, herein, we propose a method to covalently link cDNA display molecules with their target proteins using light irradiation. We designed a new puromycin DNA linker that contains a photocrosslinking nucleic acid and prepared cDNA display molecules using the linker. Target proteins were also labeled with a short single-stranded DNA that should transiently hybridize with the linker. Upon ultraviolet (UV) light irradiation, cDNA display molecules encoding correct peptide aptamers made stable crosslinked products with the target proteins in solution, while display molecules encoding control peptides did not. Although further optimization and improvement is necessary, the results pave the way for efficient selection of peptide aptamers in multimolecular crowding biosystems.

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Discovery of a Covalent Kinase Inhibitor from a DNA-Encoded Small-Molecule Library × Protein Library Selection

Cited by 70 publications

References 31 publications

DNA-Encoded Chemical Libraries: A Selection System Based on Endowing Organic Compounds with Amplifiable Information

DNA-Encoded Chemical Libraries: A Selection System Based on Endowing Organic Compounds with Amplifiable Information

Nucleic Acid‐Barcoding Technologies: Converting DNA Sequencing into a Broad‐Spectrum Molecular Counter

Photocrosslinking of cDNA Display Molecules with Their Target Proteins as a New Strategy for Peptide Selection

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