Kinase inhibitors: the road ahead

Nature Reviews Drug Discovery, Journal Year: 2018, Volume and Issue: 17(5), P. 353 - 377

Published: March 16, 2018

Language: Английский

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Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

Journal of Medicinal Chemistry, Journal Year: 2018, Volume and Issue: 62(12), P. 5673 - 5724

Published: Dec. 19, 2018

Targeted covalent inhibitors (TCIs) are designed to bind poorly conserved amino acids by means of reactive groups, the so-called warheads. Currently, targeting noncatalytic cysteine residues with acrylamides and other α,β-unsaturated carbonyl compounds is predominant strategy in TCI development. The recent ascent drugs has stimulated considerable efforts characterize alternative warheads for covalent-reversible irreversible engagement as well acids. This Perspective article provides an overview warheads-beyond amides-recently used design targeted ligands. Promising groups that have not yet demonstrated their utility development also highlighted. Special emphasis placed on discussion reactivity case studies illustrating applications medicinal chemistry chemical biology.

Language: Английский

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Trends in kinase drug discovery: targets, indications and inhibitor design

Nature Reviews Drug Discovery, Journal Year: 2021, Volume and Issue: 20(11), P. 839 - 861

Published: Aug. 5, 2021

Language: Английский

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Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening

Journal of the American Chemical Society, Journal Year: 2019, Volume and Issue: 141(22), P. 8951 - 8968

Published: May 7, 2019

Covalent probes can display unmatched potency, selectivity, and duration of action; however, their discovery is challenging. In principle, fragments that irreversibly bind target overcome the low affinity limits reversible fragment screening, but such electrophilic were considered nonselective rarely screened. We hypothesized mild electrophiles might selectivity challenge constructed a library 993 mildly fragments. characterized this by new high-throughput thiol-reactivity assay screened them against 10 cysteine-containing proteins. Highly reactive promiscuous rare could be easily eliminated. contrast, we found hits for most targets. Combining our approach with crystallography allowed rapid progression to potent selective two enzymes, deubiquitinase OTUB2 pyrophosphatase NUDT7. No inhibitors previously known either. This study highlights potential electrophile-fragment screening as practical efficient tool covalent-ligand discovery.

Language: Английский

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Advances in covalent kinase inhibitors

Chemical Society Reviews, Journal Year: 2020, Volume and Issue: 49(9), P. 2617 - 2687

Published: Jan. 1, 2020

Over the past decade, covalent kinase inhibitors (CKI) have seen a resurgence in drug discovery. Covalency affords unique set of advantages as well challenges relative to their non-covalent counterpart. After reversible protein target recognition and binding, irreversibly modify proximal nucleophilic residue on via reaction with an electrophile. To date, acrylamide group remains predominantly employed electrophile CKI development, its incorporation majority clinical candidates FDA approved therapies. Nonetheless, recent years considerable efforts ensued characterize alternative electrophiles that exhibit irreversible or reversibly binding mechanisms towards cysteine thiols other amino acids. This review article provides comprehensive overview CKIs reported literature over decade period, 2007-2018. Emphasis is placed rationale behind warhead choice, optimization approach, inhibitor design. Current are also highlighted, addition detailed analysis common trends themes observed within listed data set.

Language: Английский

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A proteome-wide atlas of lysine-reactive chemistry

Nature Chemistry, Journal Year: 2021, Volume and Issue: 13(11), P. 1081 - 1092

Published: Sept. 9, 2021

Language: Английский

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Recent Advances in Selective and Irreversible Covalent Ligand Development and Validation

Cell chemical biology, Journal Year: 2019, Volume and Issue: 26(11), P. 1486 - 1500

Published: Oct. 17, 2019

Language: Английский

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Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors

Journal of Biological Chemistry, Journal Year: 2022, Volume and Issue: 298(8), P. 102247 - 102247

Published: July 10, 2022

Protein kinases are key components in cellular signaling pathways as they carry out the phosphorylation of proteins, primarily on Ser, Thr, and Tyr residues. The catalytic activity protein is regulated, can be thought molecular switches that controlled through protein-protein interactions post-translational modifications. exhibit diverse structural mechanisms regulation have been fascinating subjects for biologists from first crystal structure a kinase over 30 years ago, to recent insights into assemblies enabled by breakthroughs cryo-EM. high-priority targets drug discovery oncology other disease settings, inhibitors transformed outcomes specific groups patients. Most ATP competitive, deriving potency occupying deep hydrophobic pocket at heart domain. Selectivity depends exploiting differences between amino acids line site exploring surrounding pockets present inactive states kinase. More recently, allosteric outside being targeted achieve high selectivity overcome resistance current therapeutics. Here, we review regulatory features family, describe different types inhibitors, highlight examples where understanding has gone hand with development inhibitors.

Language: Английский

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Reversible lysine-targeted probes reveal residence time-based kinase selectivity

Nature Chemical Biology, Journal Year: 2022, Volume and Issue: 18(9), P. 934 - 941

Published: May 19, 2022

Language: Английский

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Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(10), P. 7668 - 7758

Published: May 7, 2024

Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with variety new targeted drugs having been approved recent years. A key feature such molecules is an intrinsically reactive group, typically weak electrophile, which enables irreversible or reversible formation bond specific amino acid target protein. This often called "warhead", critical determinant ligand's activity, selectivity, general biological properties. In 2019, we summarized emerging re-emerging warhead chemistries to cysteine acids (Gehringer, M.; Laufer, S. A. J. Med. Chem. 62, 5673−5724; DOI: 10.1021/acs.jmedchem.8b01153). Since then, field has rapidly evolved. Here discuss progress on warheads made since our last Perspective their application medicinal chemistry chemical biology.

Language: Английский

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