Discovery of a Potent BTK Inhibitor with a Novel Binding Mode by Using Parallel Selections with a DNA‐Encoded Chemical Library

Cuozzo, John W.; Centrella, Paolo A.; Gikunju, Diana; Habeshian, Sevan; Hupp, Christopher D.; Keefe, Anthony D.; Sigel, Eric A.; Soutter, Holly H.; Thomson, Heather A.; Zhang, Ying; Clark, Matthew

doi:10.1002/cbic.201600573

Cited by 65 publications

(61 citation statements)

References 34 publications

(17 reference statements)

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“…However, conventional technologies based on affinity capture methods are quite reliable for the isolation of nanomolar binders from encoded libraries, if and when they are present in the repertoire [42,61].…”

Section: Ligands Isolated From Dna-encoded Chemical Librariesmentioning

confidence: 99%

DNA‐encoded chemical libraries – achievements and remaining challenges

et al. 2018

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Edited by Wilhelm JustDNA-encoded chemical libraries (DECLs) are collections of compounds, individually coupled to DNA tags serving as amplifiable identification barcodes. Since individual compounds can be identified by the associated DNA tag, they can be stored as a mixture, allowing the synthesis and screening of combinatorial libraries of unprecedented size, facilitated by the implementation of split-and-pool synthetic procedures or other experimental methodologies. In this review, we briefly present relevant concepts and technologies, which are required for the implementation and interpretation of screening procedures with DNA-encoded chemical libraries. Moreover, we illustrate some success stories, detailing how novel ligands were discovered from encoded libraries. Finally, we critically review what can realistically be achieved with the technology at the present time, highlighting challenges and opportunities for the future.

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Section: Ligands Isolated From Dna-encoded Chemical Librariesmentioning

confidence: 99%

DNA‐encoded chemical libraries – achievements and remaining challenges

et al. 2018

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“…This substructure-seeking strategy has become an important part of DEL analysis and has been adopted by many other practitioners. 10,12,15−19…”

Section: Introductionmentioning

confidence: 99%

Quantitative Comparison of Enrichment from DNA-Encoded Chemical Library Selections

et al. 2019

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DNA-encoded chemical libraries (DELs) provide a high-throughput and cost-effective route for screening billions of unique molecules for binding affinity for diverse protein targets. Identifying candidate compounds from these libraries involves affinity selection, DNA sequencing, and measuring enrichment in a sample pool of DNA barcodes. Successful detection of potent binders is affected by many factors, including selection parameters, chemical yields, library amplification, sequencing depth, sequencing errors, library sizes, and the chosen enrichment metric. To date, there has not been a clear consensus about how enrichment from DEL selections should be measured or reported. We propose a normalized z-score enrichment metric using a binomial distribution model that satisfies important criteria that are relevant for analysis of DEL selection data. The introduced metric is robust with respect to library diversity and sampling and allows for quantitative comparisons of enrichment of n-synthons from parallel DEL selections. These features enable a comparative enrichment analysis strategy that can provide valuable information about hit compounds in early stage drug discovery.

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“…Recently, Cuozzo et al. published the discovery of a potent covalent inhibitor of Bruton's tyrosine kinase (BTK), with picomolar IC 50 value from a single DNA encoded library …”

Section: Figurementioning

confidence: 99%

“…Recently,C uozzo et al published the discoveryo fapotent covalenti nhibitor of Bruton's tyrosine kinase (BTK), with picomolar IC 50 value from as ingle DNA encoded library. [10] Here, we describe the construction of aD NA-encoded selfassembling chemical library,f ormed by combination of 265 559 buildingb locks, yieldinga nE SAC libraryw ith 148 135 members. The library was designed to incorporate building blocks, whichw ere potentially capable of forming covalenti nteractions with certain amino acid residues.…”

mentioning

confidence: 99%

A Specific and Covalent JNK‐1 Ligand Selected from an Encoded Self‐Assembling Chemical Library

Zimmermann

Rieder

Bajic

et al. 2017

Chemistry A European J

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We describe the construction of a DNA-encoded chemical library comprising 148'135 members, generated through the self-assembly of two sub-libraries, containing 265 and 559 members, respectively. The library was designed to contain building blocks potentially capable of forming covalent interactions with target proteins. Selections performed against JNK1, a kinase containing a conserved cysteine residue close to the ATP binding site, revealed the preferential enrichment of a 2-phenoxynicotinic acid moiety (building block A82) and a 4-(3,4-difluorophenyl)-4-oxobut-2-enoic acid moiety (building block B272). When the two compounds were joined by a short PEG linker, the resulting bidentate binder (A82-L-B272) was able to covalently modify JNK1 in the presence of a large molar excess of glutathione (0.5 mM), used to simulate intracellular reducing conditions. By contrast, derivatives of the individual building blocks were not able to covalently modify JNK1 in the same experimental conditions. The A82-L-B272 ligand was selective over related kinases (BTK and GAK), which also contain targetable cysteine residues in the vicinity of the active site. A distinction is often made between "single pharmacophore" and "dual pharmacophore" chemical libraries. In the first case, individual compounds (no matter how complex) are coupled to a DNA fragment, which serves as amplifiable identification barcode. In the second case, two building blocks are simultaneously connected to the extremities of complementary DNA strands, thus enabling the formation of combinatorial libraries by the self-assembly of oligonucleotide conjugates. [3] We have recently described a strategy for the encoding of dualpharmacophore libraries (also called "encoded self-assembling chemical libraries", or ESAC libraries), which was compatible with library decoding procedures, based on high-throughput DNA sequencing. [4] ESAC libraries may facilitate the identification of synergistic building blocks, which recognize adjacent pockets on target proteins of interest. These chemical moieties need to be subsequently connected through a suitable chemical linker, in order to display protein binding in the absence of DNA. [4,5,6] Encoded chemical libraries have previously been used for the discovery of covalent protein binders. For example, Nicolas Winssinger and coworkers previously reported the identification of reversible and irreversible covalent binders of bromodomain, [7] kinases, [8] proteases and phosphatases [9] from both DNA and PNA encoded chemical libraries. Recently, Cuozzo et al. 4 published the discovery of a potent covalent inhibitor of Bruton's tyrosine kinase (BTK), with picomolar IC 50 value from a single DNA encoded library. [10] Here, we describe the construction of a DNA-encoded self-assembling chemical library, formed by combination of 265 x 559 building blocks, yielding an ESAC library with 148'135 members. The library was designed to incorporate building blocks, which were potentially capable of forming covalent interactions with ce...

show abstract

Discovery of a Potent BTK Inhibitor with a Novel Binding Mode by Using Parallel Selections with a DNA‐Encoded Chemical Library

Cited by 65 publications

References 34 publications

DNA‐encoded chemical libraries – achievements and remaining challenges

DNA‐encoded chemical libraries – achievements and remaining challenges

Quantitative Comparison of Enrichment from DNA-Encoded Chemical Library Selections

A Specific and Covalent JNK‐1 Ligand Selected from an Encoded Self‐Assembling Chemical Library

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