Discovering Cell‐Targeting Ligands and Cell‐Surface Receptors by Selection of DNA‐Encoded Chemical Libraries against Cancer Cells without Predefined Targets

Angewandte Chemie, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 11, 2025

Abstract Small molecules that can bind to specific cells have broad application in cancer diagnosis and treatment. Screening large chemical libraries against live is an effective strategy for discovering cell‐targeting ligands. The DNA‐encoded library (DEL or DECL) technology has emerged as a robust tool drug discovery been successfully utilized identifying ligands biological targets. However, nearly all DEL selections predefined targets, while target‐agnostic interrogating the entire cell surface remain underexplored. Herein, we systematically optimized cell‐based selection method without A 104.96‐million‐member was selected MDA‐MB‐231 MCF‐7 breast cells, representing high low metastatic properties, respectively, which led identification of cell‐specific small molecules. We further demonstrated applications these photodynamic therapy targeted delivery. Finally, leveraging DNA tag compounds, identified α‐enolase (ENO1) receptor one targeting more aggressive cells. Overall, this work offers efficient approach molecule by using DELs demonstrates be useful identify receptors on

Language: Английский

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Discovering Cell‐Targeting Ligands and Cell‐Surface Receptors by Selection of DNA‐Encoded Chemical Libraries against Cancer Cells without Predefined Targets

Angewandte Chemie International Edition, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 11, 2025

Abstract Small molecules that can bind to specific cells have broad application in cancer diagnosis and treatment. Screening large chemical libraries against live is an effective strategy for discovering cell‐targeting ligands. The DNA‐encoded library (DEL or DECL) technology has emerged as a robust tool drug discovery been successfully utilized identifying ligands biological targets. However, nearly all DEL selections predefined targets, while target‐agnostic interrogating the entire cell surface remain underexplored. Herein, we systematically optimized cell‐based selection method without A 104.96‐million‐member was selected MDA‐MB‐231 MCF‐7 breast cells, representing high low metastatic properties, respectively, which led identification of cell‐specific small molecules. We further demonstrated applications these photodynamic therapy targeted delivery. Finally, leveraging DNA tag compounds, identified α‐enolase (ENO1) receptor one targeting more aggressive cells. Overall, this work offers efficient approach molecule by using DELs demonstrates be useful identify receptors on

Language: Английский

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Identification of Structurally Novel KRAS^G12C Inhibitors through Covalent DNA-Encoded Library Screening

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 11, 2025

Covalent inhibition of the KRASG12C oncoprotein has emerged as a promising therapeutic approach for treatment nonsmall cell lung cancer (NSCLC). The identification inhibitors typically relied on high-throughput screening (HTS) libraries cysteine-reactive small molecules or attachment warheads to noncovalent binders KRAS. Such approaches have historically been limited in size and diversity that could be effectively screened. DNA-encoded library (DEL) accelerate preparation incredibly large diverse chemical libraries. Here, we describe design synthesis covalent DEL screen ∼16 million compounds against KRASG12C. We additionally hit identification, validation, structure-based optimization culminated series structurally novel, potent, selective with good pharmacokinetic profiles vivo pharmacodynamic effects.

Language: Английский

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Photochemical-Promoted Cross-Coupling Reaction of Alkyl Boronate Esters with DNA-Conjugated Aryl Bromides for DNA-Encoded Library Synthesis

Bioconjugate Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 27, 2025

The C(sp2)-C(sp3) cross-coupling reaction is an effective way to increase the C(sp3) content in compound collections for drug discovery, enhancing molecular diversity and offering a unique chemistry starting point. In this study, we report mild, DNA-compatible, off-DNA-inert photochemical inspired by amino radical transfer strategy. This method demonstrates broad substrate scopes DNA-encoded library (DEL) constructions, utilizing commonly available structures on DNA diverse alkyl boronate ester building blocks, which have not been widely applied current DEL chemical space.

Language: Английский

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Covalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

The COVID-19 pandemic, exacerbated by persistent viral mutations, underscored the urgent need for diverse inhibitors targeting multiple proteins. In this study, we utilized covalent DNA-encoded libraries to discover innovative triazine-based 3-chymotrypsin-like protease (3CLpro, Nsp5) and papain-like (PLpro) domains of Nsp3, as well novel non-nucleoside nonstructural protein 12 (Nsp12, RdRp). Optimization through molecular docking medicinal chemistry led development LU9, a nonpeptide 3CLpro inhibitor with an IC50 0.34 μM, LU10, whose crystal structure showed distinct binding mode within active site. X-ray cocrystal SARS-CoV-2 PLpro in complex XD5 uncovered previously unexplored site adjacent catalytic pocket. Additionally, Nsp12 XJ5 achieved potency 0.12 μM following comprehensive structure–activity relationship analysis optimization. Molecular dynamics revealed potential mode. These compounds offer valuable chemical probes target validation represent promising candidates antiviral therapies.

Language: Английский

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