Strategies for developing DNA-encoded libraries beyond binding assays

Huang, Yiran; Li, Yizhou; Li, Xiaoyu

doi:10.1038/s41557-021-00877-x

Cited by 76 publications

(68 citation statements)

References 146 publications

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“…Since its conception by Lerner and Brenner in 1992, [ 1 ] DNA‐encoded library (DEL), which provides a general way to bridge chemistry and biology, [ 2 , 3 ] has become one of the most powerful techniques for the discovery of hit compounds and/or bioactive probes in medicinal chemistry and chemical biology. Generally, DEL has significant advantages such as a huge library size, comprehensive chemical space, and lower cost.…”

Section: Introductionmentioning

confidence: 99%

Metal‐Free and Open‐Air Arylation Reactions of Diaryliodonium Salts for DNA‐Encoded Library Synthesis

Tan

Zhang

et al. 2022

Advanced Science

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A successful DNA‐encoded library (DEL) will consist of diverse skeletons and cover chemical space as comprehensive as possible to fully realize its potential in drug discovery and chemical biology. However, the lack of versatile on‐DNA arylation methods for phenols that are less nucleophilic and reactive poses a great hurdle for DEL to include diaryl ether, a privileged chemotype in pharmaceuticals and natural products. This work describes the use of “substrate activation” approach to address the arylation of DNA‐conjugated phenols. Diaryliodonium salt, a highly electrophilic and reactive arylation reagent, is employed as Ar+ sources to ensure highly selective on‐DNA arylation of phenols and oximes with both high yields and DNA fidelity. Notably, the new on‐DNA arylation reaction can be applied to the late‐stage modification of peptides containing tyrosine side‐chain and to synthesize DNA‐tagged analogues of existing drug molecules such as sorafenib, a known pan‐kinase inhibitor. The new on‐DNA diaryliodonium salts chemistry affords a greater flexibility in DEL design and synthesis.

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Section: Introductionmentioning

confidence: 99%

Metal‐Free and Open‐Air Arylation Reactions of Diaryliodonium Salts for DNA‐Encoded Library Synthesis

Tan

Zhang

et al. 2022

Advanced Science

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“…For the reasons mentioned previously, alternative therapeutic strategies directed towards the development of molecules targeting non-ATP binding sites have emerged and are becoming more popular ( Wu et al, 2015 ; Lu et al, 2019 ; Lu et al, 2020 ). The DEL technology might be particularly adapted to identify allosteric modulators and to target cryptic pockets in general, due to its screening concept that is based solely on binding affinity ( Schwab et al, 2000 ; Gironda-Martinez et al, 2021 ; Huang et al, 2022 ). With this approach, a very large number of compounds this was mentioned just before covalently tagged with a unique and specific DNA sequence are mixed with the immobilized protein target in a single tube.…”

Section: Dna-encoded Libraries and Non-biased Approaches To Tackle Al...mentioning

confidence: 99%

The protein kinase CK1: Inhibition, activation, and possible allosteric modulation

Sunkari

Meijer

Flajolet

2022

Front. Mol. Biosci.

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Protein kinases play a vital role in biology and deregulation of kinases is implicated in numerous diseases ranging from cancer to neurodegenerative diseases, making them a major target class for the pharmaceutical industry. However, the high degree of conservation that exists between ATP-binding sites among kinases makes it difficult for current inhibitors to be highly specific. In the context of neurodegeneration, several groups including ours, have linked different kinases such as CK1 and Alzheimer’s disease for example. Strictly CK1-isoform specific regulators do not exist and known CK1 inhibitors are inhibiting the enzymatic activity, targeting the ATP-binding site. Here we review compounds known to target CK1, as well as other inhibitory types that could benefit CK1. We introduce the DNA-encoded library (DEL) technology that might represent an interesting approach to uncover allosteric modulators instead of ATP competitors. Such a strategy, taking into account known allosteric inhibitors and mechanisms, might help designing modulators that are more specific towards a specific kinase, and in the case of CK1, toward specific isoforms.

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“…During the past decade, the use of DEL technology provided a great opportunity to identify drug-like compounds that can bind selectively to a variety of target proteins ( Deng et al, 2012 ; Gentile et al, 2012 ; Disch et al, 2013 ; Samain et al, 2015 ; Seigal et al, 2015 ; Harris et al, 2016 ; Belyanskaya et al, 2017 ; Dawadi et al, 2020 ; Chamakuri et al, 2021 ). More recently, a number of different powerful applications leveraging the DEL technology have been proposed ( Huang et al, 2022 ; Sunkari et al, 2022 ; Zhao et al, 2022 ). To expand the chemical space of these DNA-Encoded Libraries, a greater variety of DNA-Compatible reactions is required.…”

Section: Introductionmentioning

confidence: 99%

DNA-Compatible Suzuki-Miyaura Cross-Coupling Reaction of Aryl Iodides With (Hetero)Aryl Boronic Acids for DNA-Encoded Libraries

et al. 2022

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An efficient method for the C-C bond formation via water soluble Na2PdCl4/sSPhos mediated Suzuki-Miyaura cross-coupling reaction of DNA-conjugated aryl iodide with (het)aryl boronic acids has been developed. This reaction proceeds at 37°C in water and acetonitrile (4:1) system. We also demonstrated that numerous aromatic and heteroaromatic boronic acids of different electronic natures, and harboring various functional groups, were highly compatible providing the desired coupling products in good to excellent yields. This DNA-compatible Suzuki-Miyaura cross-coupling reaction has strong potential to construct DNA-Encoded Libraries (DELs) in the context of drug discovery.

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Strategies for developing DNA-encoded libraries beyond binding assays

Cited by 76 publications

References 146 publications

Metal‐Free and Open‐Air Arylation Reactions of Diaryliodonium Salts for DNA‐Encoded Library Synthesis

Metal‐Free and Open‐Air Arylation Reactions of Diaryliodonium Salts for DNA‐Encoded Library Synthesis

The protein kinase CK1: Inhibition, activation, and possible allosteric modulation

DNA-Compatible Suzuki-Miyaura Cross-Coupling Reaction of Aryl Iodides With (Hetero)Aryl Boronic Acids for DNA-Encoded Libraries

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