ERK1/2 inhibitors: New weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway

Pharmacology & Therapeutics, Год журнала: 2018, Номер 187, С. 45 - 60

Опубликована: Фев. 15, 2018

Язык: Английский

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Reactive-cysteine profiling for drug discovery

Current Opinion in Chemical Biology, Год журнала: 2019, Номер 50, С. 29 - 36

Опубликована: Март 18, 2019

Язык: Английский

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Assessing Lysine and Cysteine Reactivities for Designing Targeted Covalent Kinase Inhibitors

Journal of the American Chemical Society, Год журнала: 2019, Номер 141(16), С. 6553 - 6560

Опубликована: Апрель 4, 2019

Targeted covalent inhibitor design is gaining increasing interest and acceptance. A typical kinase targets a reactive cysteine; however, this strategy limited by the low abundance of cysteine acquired drug resistance from point mutations. Inspired recent development lysine-targeted chemical probes, we asked if nucleophilic (reactive) catalytic lysines are common on basis published crystal structures human kinome. Using newly developed pKa prediction tool based continuous constant pH molecular dynamics, eight unique kinases various groups were retrospectively prospectively predicted to be nucleophilic, when in rare DFG-out/αC-out type conformation. Importantly, other as well cysteines at locations also identified. On findings, proposed new which selective II reversible inhibitors modified highly selective, inhibitors. Traditional drugs discovered serendipitously; presented tool, can assess reactivities any potentially targetable residues, may accelerate rational discovery Another significant finding work that adopt neutral charged states physiological pH, respectively. This shift current paradigm computational studies kinases, assume fixed solution protonation states.

Язык: Английский

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Covalent Inhibitors of Protein–Protein Interactions Targeting Lysine, Tyrosine, or Histidine Residues

Journal of Medicinal Chemistry, Год журнала: 2019, Номер 62(11), С. 5616 - 5627

Опубликована: Май 16, 2019

We have recently reported a series of Lys-covalent agents targeting the BIR3 domain X-linked inhibitor apoptosis protein (XIAP) using benzamide-sulfonyl fluoride warhead. Using XIAP as model system, we further investigated variety additional warheads that can be easily incorporated into binding peptides and analyzed their ability to form covalent adducts with lysine other amino acids, including tyrosine, histidine, serine, threonine, biochemical biophysical assays. Moreover, tested aqueous, plasma stability, cell permeability, cellular efficacy most effective agents. These studies identified aryl-fluoro sulfates likely suitable electrophiles effectively Lys, Tyr, His residues, given these were permeable stable in aqueous buffer plasma. Our contain number general findings open new possible avenues for design potent protein–protein interaction antagonists.

Язык: Английский

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Chemoproteomics and Chemical Probes for Target Discovery

Trends in biotechnology, Год журнала: 2018, Номер 36(12), С. 1275 - 1286

Опубликована: Июль 13, 2018

Язык: Английский

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A road map for prioritizing warheads for cysteine targeting covalent inhibitors

European Journal of Medicinal Chemistry, Год журнала: 2018, Номер 160, С. 94 - 107

Опубликована: Окт. 6, 2018

Язык: Английский

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Light-Activatable, 2,5-Disubstituted Tetrazoles for the Proteome-wide Profiling of Aspartates and Glutamates in Living Bacteria

ACS Central Science, Год журнала: 2020, Номер 6(4), С. 546 - 554

Опубликована: Апрель 13, 2020

Covalent inhibitors have recently seen a resurgence of interest in drug development. Nevertheless, compounds, which do not rely on an enzymatic activity, almost exclusively been developed to target cysteines. Expanding the scope other amino acids would be largely facilitated by ability globally monitor their engagement covalent inhibitors. Here, we present use light-activatable 2,5-disubstituted tetrazoles that allow quantifying 8971 aspartates and glutamates bacterial proteome with excellent selectivity. Using these probes, competitively map binding sites two isoxazolium salts introduce hydrazonyl chlorides as new class carboxylic-acid-directed protein ligands. As probes are unreactive prior activation, they global profiling even living Gram-positive Gram-negative bacteria. Taken together, this method proteome-wide will lay foundation efficiently develop targeting acids.

Язык: Английский

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Isotopically Labeled Desthiobiotin Azide (isoDTB) Tags Enable Global Profiling of the Bacterial Cysteinome

Angewandte Chemie International Edition, Год журнала: 2019, Номер 59(7), С. 2829 - 2836

Опубликована: Ноя. 29, 2019

Abstract Rapid development of bacterial resistance has led to an urgent need find new druggable targets for antibiotics. In this context, residue‐specific chemoproteomic approaches enable proteome‐wide identification binding sites covalent inhibitors. Described here are easily synthesized isotopically labeled desthiobiotin azide (isoDTB) tags that shortened the workflow and allowed increased coverage cysteines in systems. They were used quantify 59 % all essential proteins Staphylococcus aureus enabled discovery 88 showed high reactivity, which correlates with functional importance. Furthermore, 268 engaged by ligands identified. Inhibition HMG‐CoA synthase was verified will allow addressing mevalonate pathway through a target. Overall, broad map cysteinome obtained, facilitate antibiotics novel modes‐of‐action.

Язык: Английский

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Discovery of Cysteine-targeting Covalent Protein Kinase Inhibitors

Journal of Medicinal Chemistry, Год журнала: 2021, Номер 65(1), С. 58 - 83

Опубликована: Дек. 28, 2021

Small molecule covalent kinase inhibitors (CKIs) have entered a new era in drug discovery, which the advantage for sustained target inhibition and high selectivity. An increased understanding of binding kinetics CKIs discovery additional irreversible reversible-covalent cysteine-targeted warheads has inspired development this area. Herein, we summarize major medicinal chemistry strategies employed these representative CKIs, are categorized by location cysteine within seven main regions kinase: front region, glycine rich loop (P-loop), hinge DFG activation (A-loop), catalytic (C-loop), remote loop. The emphasis is placed on design optimization that generated addition warhead to reversible lead/inhibitor scaffold. In addition, address challenges facing area discovery.

Язык: Английский

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Covalent fragment libraries in drug discovery

Drug Discovery Today, Год журнала: 2020, Номер 25(6), С. 983 - 996

Опубликована: Апрель 13, 2020

Targeted covalent inhibitors and chemical probes have become integral parts of drug discovery approaches. Given the advantages fragment-based discovery, screening electrophilic fragments emerged as a promising alternative to discover validate novel targets generate viable starting points even for that are barely tractable. In this review, we present recent principles considerations in design fragment libraries from selection appropriate warhead through compilation library. We then summarize methodologies against surrogate models, proteins, whole proteome, or living cells. Finally, highlight applications libraries.

Язык: Английский

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