Lysine‐Targeting Covalent Inhibitors

Angewandte Chemie International Edition, Journal Year: 2017, Volume and Issue: 56(48), P. 15200 - 15209

Published: Aug. 29, 2017

Abstract Targeted covalent inhibitors have gained widespread attention in drug discovery as a validated method to circumvent acquired resistance oncology. This strategy exploits small‐molecule/protein crystal structures design tightly binding ligands with appropriately positioned electrophilic warheads. Whilst most focus has been on targeting binding‐site cysteine residues, nucleophilic lysine residues can also represent viable approach irreversible inhibition. However, owing the basicity of ϵ ‐amino group lysine, this generates number specific challenges. Herein, we review key principles for inhibitor design, give historical examples, and present recent developments that demonstrate potential future discovery.

Language: Английский

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Rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed N-acyl-N-alkyl sulfonamide

Nature Communications, Journal Year: 2018, Volume and Issue: 9(1)

Published: May 8, 2018

Selective modification of native proteins in live cells is one the central challenges recent chemical biology. As a unique bioorthogonal approach, ligand-directed chemistry recently emerged, but slow kinetics limits its scope. Here we successfully overcome this obstacle using N-acyl-N-alkyl sulfonamide as reactive group. Quantitative kinetic analyses reveal that allows for rapid lysine residue proximal to ligand binding site target protein, with rate constant ~104 M-1 s-1, comparable fastest chemistry. Despite some off-target reactions, method can selectively label both intracellular and membrane-bound endogenous proteins. Moreover, reactivity enables rational design lysine-targeted covalent inhibitor shows durable suppression activity Hsp90 cancer cells. This work provides possibilities extend inhibition approach currently being reassessed drug discovery.

Language: Английский

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Progress with covalent small-molecule kinase inhibitors

Drug Discovery Today, Journal Year: 2018, Volume and Issue: 23(3), P. 727 - 735

Published: Jan. 11, 2018

With reduced risk of toxicity and high selectivity, covalent small-molecule kinase inhibitors (CSKIs) have emerged rapidly. Through the lens structural system pharmacology, here we review this rapid progress by considering design strategies challenges opportunities offered current CSKIs.

Language: Английский

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A Heck–Matsuda Process for the Synthesis of β‐Arylethenesulfonyl Fluorides: Selectively Addressable Bis‐electrophiles for SuFEx Click Chemistry

Angewandte Chemie International Edition, Journal Year: 2016, Volume and Issue: 55(45), P. 14155 - 14158

Published: Oct. 10, 2016

Abstract A Heck–Matsuda process for the synthesis of otherwise difficult to access compounds, β‐arylethenesulfonyl fluorides, is described. Ethenesulfonyl fluoride (i.e., vinylsulfonyl fluoride, or ESF) undergoes β‐arylation with stable and readily prepared arenediazonium tetrafluoroborates in presence catalyst palladium(II) acetate afford E ‐isomer sulfonyl analogues cinnamoyl 43–97 % yield. The fluorides are found be selectively addressable bis‐electrophiles sulfur(VI) exchange (SuFEx) click chemistry, which either alkenyl moiety group can exclusive site nucleophilic attack under defined conditions, making these rather simple cores attractive covalent drug discovery.

Language: Английский

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Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

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The Ascension of Targeted Covalent Inhibitors

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(8), P. 5886 - 5901

Published: April 19, 2022

Covalent drugs have made a major impact on human health but until recently were shunned by the pharmaceutical industry over concerns about potential for toxicity. A resurgence has occurred driven clinical success of targeted covalent inhibitors (TCIs), with eight approved past decade. The opportunity to create unique exploiting mechanism action enabled clinically decisive target product profiles be achieved. TCIs revolutionized treatment paradigm non-small-cell lung cancer and chronic lymphocytic leukemia. This Perspective will highlight financial this class provide early insight into toxicity, key factor that had hindered progress in field. Further innovation TCI approach, including expanding beyond cysteine-directed electrophiles, kinases, cancer, highlights broad deliver new generation breakthrough therapies.

Language: Английский

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Bruton tyrosine kinase inhibitors for multiple sclerosis

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(5), P. 289 - 304

Published: April 13, 2023

Language: Английский

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Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: March 28, 2023

Abstract Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 essential for viral replication. In addition, PLpro dysregulates the host immune response cleaving ubiquitin and interferon-stimulated gene 15 protein proteins. As a result, promising target inhibition small-molecule therapeutics. Here we design series covalent inhibitors introducing peptidomimetic linker reactive electrophile onto analogs noncovalent inhibitor GRL0617. most potent compound inhibits with k inact /K I = 9,600 M −1 s , achieves sub-μM EC 50 values against three variants in mammalian cell lines, does not inhibit panel human deubiquitinases (DUBs) at >30 μM concentrations inhibitor. An X-ray co-crystal structure bound validates our strategy establishes molecular basis selectivity structurally similar DUBs. These findings present an opportunity further development inhibitors.

Language: Английский

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Recent Advances in Covalent Drug Discovery

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(5), P. 663 - 663

Published: April 28, 2023

In spite of the increasing number biologics license applications, development covalent inhibitors is still a growing field within drug discovery. The successful approval some protein kinase inhibitors, such as ibrutinib (BTK inhibitor) and dacomitinib (EGFR inhibitor), very recent discovery for viral proteases, boceprevir, narlaprevir, nirmatrelvir, represent new milestone in development. Generally, formation bonds that target proteins can offer drugs diverse advantages terms selectivity, resistance, administration concentration. most important factor electrophile (warhead), which dictates reactivity, type binding (i.e., reversible or irreversible) be modified/optimized through rational designs. Furthermore, are becoming more common proteolysis, targeting chimeras (PROTACs) degrading proteins, including those currently considered to ‘undruggable’. aim this review highlight current state inhibitor development, short historical overview examples applications PROTAC technologies treatment SARS-CoV-2 virus.

Language: Английский

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Advancements and novel approaches in modified AutoDock Vina algorithms for enhanced molecular docking

Results in Chemistry, Journal Year: 2024, Volume and Issue: 7, P. 101319 - 101319

Published: Jan. 1, 2024

Molecular docking plays a crucial role in modern drug discovery by facilitating the prediction of interactions between small molecules and biomolecular targets. AutoDock Vina (Vina) has earned its reputation as leading software thanks to effective energy-based scoring system user-friendly interface. However, growing demands computational biology have prompted investigations into improvements for Vina, range algorithmic enhancements. This systematic review explores recent developments achieved molecular docking. These modifications include hybrid parallelization methods utilizing high-performance computing innovative functions integrated with machine learning. The examines difficulties possibilities associated these adapted algorithms, shedding light on their diverse origins potential collaboration across chemistry, learning, structural biology, emerging technologies.

Language: Английский

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