From DEL Selections to Validated Hits to Clinical Leads

Marcaurelle, Lisa A.; Tear, Westley; Yao, Gang

doi:10.1007/7355_2022_150

Topics in Medicinal Chemistry

2022

DOI: 10.1007/7355_2022_150

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From DEL Selections to Validated Hits to Clinical Leads

Lisa A. Marcaurelle¹,

Westley Tear²,

Gang Yao³

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2024

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Cited by 2 publications

(1 citation statement)

References 84 publications

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“…Because it is inexpensive, is efficient, and enables the use of a plethora of chemical building blocks and reaction types (15), DEL technology has been routinely implemented for small-molecule drug discovery in both industry and academia (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). It is increasingly filling the pharmaceutical companies' pipelines (38) and swiftly providing valuable chemical probes for basic cellular and molecular biology and proteomics research (16,39); in contrast to biomacromolecules, small molecules exhibit distinct pharmacokinetic advantages and are typically cell permeable (40).…”

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confidence: 99%

Highly pure DNA-encoded chemical libraries by dual-linker solid-phase synthesis

Keller,

Petrov,

Gloger

et al. 2024

Science

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The first drugs discovered using DNA-encoded chemical library (DEL) screens have entered late-stage clinical development. However, DEL technology as a whole still suffers from poor chemical purity resulting in suboptimal performance. In this work, we report a technique to overcome this issue through self-purifying release of the DEL after magnetic bead–based synthesis. Both the first and last building blocks of each assembled library member were linked to the beads by tethers that could be cleaved by mutually orthogonal chemistry. Sequential cleavage of the first and last tether, with washing in between, ensured that the final library comprises only the fully complete compounds. The outstanding purity attained by this approach enables a direct correlation of chemical display and encoding, allows for an increased chemical reaction scope, and facilitates the use of more diversity elements while achieving greatly improved signal-to-noise ratios in selections.

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mentioning

confidence: 99%

Highly pure DNA-encoded chemical libraries by dual-linker solid-phase synthesis

Keller,

Petrov,

Gloger

et al. 2024

Science

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Discovery, Characterization, and Structure of a Cell Active PAD2 Inhibitor Acting through a Novel Allosteric Mechanism

Byrnes,

Choi,

Balbo

et al. 2024

ACS Chem. Biol.

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Peptidyl arginine deiminases (PADs) are important enzymes in many diseases, especially those involving inflammation and autoimmunity. Despite many years of effort, developing isoform-specific inhibitors has been a challenge. We describe herein the discovery of a potent, noncovalent PAD2 inhibitor, with selectivity over PAD3 and PAD4, from a DNA-encoded library. The biochemical and biophysical characterization of this inhibitor and two noninhibitory binders indicated a novel, Ca 2+ competitive mechanism of inhibition. This was confirmed via X-ray crystallographic analysis. Finally, we demonstrate that this inhibitor selectively inhibits PAD2 in a cellular context.

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From DEL Selections to Validated Hits to Clinical Leads

Cited by 2 publications

References 84 publications

Highly pure DNA-encoded chemical libraries by dual-linker solid-phase synthesis

Highly pure DNA-encoded chemical libraries by dual-linker solid-phase synthesis

Discovery, Characterization, and Structure of a Cell Active PAD2 Inhibitor Acting through a Novel Allosteric Mechanism

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