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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Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Oct. 7, 2020

Abstract COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through combined mass spectrometry X-ray approach SARS-CoV-2 main protease, one two cysteine viral proteases essential replication. Our crystallographic identified 71 hits that span entire active site, as well 3 at dimer interface. These structures reveal routes to rapidly develop more potent inhibitors merging covalent fragment hits; series low-reactivity, tractable progressed discover improved binders. offer unprecedented structural reactivity information on-going structure-based drug design protease.

Language: Английский

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An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells

Cell, Journal Year: 2020, Volume and Issue: 182(4), P. 1009 - 1026.e29

Published: July 29, 2020

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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Covalent inhibitors design and discovery

European Journal of Medicinal Chemistry, Journal Year: 2017, Volume and Issue: 138, P. 96 - 114

Published: June 10, 2017

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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Fibroblast Growth Factor Receptors (FGFRs): Structures and Small Molecule Inhibitors

Cells, Journal Year: 2019, Volume and Issue: 8(6), P. 614 - 614

Published: June 18, 2019

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases expressed on the cell membrane that play crucial roles in both developmental and adult cells. Dysregulation FGFRs has been implicated wide variety cancers, such as urothelial carcinoma, hepatocellular ovarian cancer lung adenocarcinoma. Due to their functional importance, have considered promising drug targets for therapy various cancers. Multiple small molecule inhibitors targeting this developed, some them clinical trials. Furthermore, pan-FGFR inhibitor erdafitinib (JNJ-42756493) recently approved by U.S. Food Drug Administration (FDA) treatment metastatic or unresectable carcinoma (mUC). This review summarizes structure FGFR, especially its kinase domain, development FGFR inhibitors.

Language: Английский

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Covalent Inhibition in Drug Discovery

ChemMedChem, Journal Year: 2019, Volume and Issue: 14(9), P. 889 - 906

Published: Feb. 28, 2019

Although covalent inhibitors have been used as therapeutics for more than a century, there has general resistance in the pharmaceutical industry against their further development due to safety concerns. This inclination recently reverted after of wide variety address human health conditions along with US Food and Drug Administration (FDA) approval several use humans. Along this exciting resurrection an old drug discovery concept, review surveys enzymes that can be targeted by treatment diseases. We focus on protein kinases, RAS proteins, few other studied extensively targets inhibition, aim challenges designing effective drugs provide suggestions area yet explored.

Language: Английский

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The Cysteinome of Protein Kinases as a Target in Drug Development

Angewandte Chemie International Edition, Journal Year: 2017, Volume and Issue: 57(16), P. 4372 - 4385

Published: Oct. 10, 2017

Abstract Drugs that function through covalent bond formation represent a considerable fraction of our repository effective medicines but safety concerns and the complexity developing inhibitors has rendered targeting less attractive strategy for rational drug design. The recent approval four kinase development highly potent probes with exceptional selectivity raised significant interest in industry academic research validated concept clinical applications. abundance cysteines at diverse positions around active site suggests large kinases can be targeted by inhibitors. Herein, we review developments this rapidly growing area highlight unique opportunities challenges strategy.

Language: Английский

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A Perspective on Multi-target Drugs for Alzheimer’s Disease

Trends in Pharmacological Sciences, Journal Year: 2020, Volume and Issue: 41(7), P. 434 - 445

Published: May 21, 2020

Language: Английский

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