Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (20 March 2023) | Viewed by 47964

Special Issue Editors


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Guest Editor
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
Interests: medicinal chemistry; chemical biology; drug design; covalent inhibitors; covalent warheads; protein kinases; chemical probes; target validation

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Guest Editor
Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
Interests: medicinal chemistry; drug discovery; chemical probes; reversible and covalent kinase inhibitors; warhead development

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Guest Editor
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
Interests: medicinal chemistry; chemical biology; drug design; chemical probes; understudied kinases; kinase inhibitors; covalent inhibitors; warhead design; target validation

Special Issue Information

Dear Colleagues,

Targeted covalent inhibitors (TCIs) have seen a resurgence in drug discovery and chemical biology. They offer a variety of benefits over classical, non-covalent targeting approaches, including an improved potency and a long duration of action. In addition to their advantages in therapeutic efficacy, TCIs can be exploited to tackle challenging targets, as has been impressively shown by the recent FDA approval of the first KRAS G12C inhibitor (Sotorasib). Addressing poorly conserved amino acids with suitable reactive groups, dubbed warheads, has further become an important strategy to promote selectivity, sometimes even between highly homologous proteins. In chemical biology, the establishment of a durable covalent link between a protein of interest and a chemical probe opens up ample opportunities for investigating the target’s biology. Significant advances in chemical proteomics have deepened our understanding of covalent ligand’s interactomes in complex biological systems. However, challenges such as a limited repertoire of warhead chemistries or the limited predictability of off-target effects and toxicities still need to be overcome. This Special Issue aims at providing an overview of the state of the art in the field of TCIs in a broader sense. In addition to the development of TCIs as chemical tools or drug candidates, it will also cover reviews and research articles on TCI warhead chemistries, chemoproteomic approaches facilitating TCI development, improved computational methods enabling TCI design, and chemical biology investigations employing specific covalent probes to interrogate biological systems.

Prof. Dr. Matthias Gehringer
Dr. Chiara Borsari
Dr. Ricardo Augusto Massarico Serafim
Guest Editors

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Keywords

  • targeted covalent inhibitors
  • chemical probes
  • drug discovery
  • drug design
  • covalent warheads
  • covalent-reversible inhibitors
  • reactivity assessment
  • covalent fragments
  • covalent degraders

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

4 pages, 177 KiB  
Editorial
Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond
by Ricardo A. M. Serafim, Matthias Gehringer and Chiara Borsari
Pharmaceuticals 2024, 17(2), 206; https://doi.org/10.3390/ph17020206 - 5 Feb 2024
Viewed by 2418
Abstract
Covalent inhibitors have experienced a revival in medicinal chemistry and chemical biology in recent decades [...] Full article

Research

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17 pages, 5154 KiB  
Article
Photocaging of Pyridinylimidazole-Based Covalent JNK3 Inhibitors Affords Spatiotemporal Control of the Binding Affinity in Live Cells
by Beate Sandra Hoffelner, Stanislav Andreev, Nicole Plank and Pierre Koch
Pharmaceuticals 2023, 16(2), 264; https://doi.org/10.3390/ph16020264 - 9 Feb 2023
Cited by 2 | Viewed by 2288
Abstract
The concept of photocaging represents a promising approach to acquire spatiotemporal control over molecular bioactivity. To apply this strategy to pyridinylimidazole-based covalent JNK3 inhibitors, we used acrylamido-N-(4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)phenyl)benzamide (1) as a lead compound to design novel covalent inhibitors [...] Read more.
The concept of photocaging represents a promising approach to acquire spatiotemporal control over molecular bioactivity. To apply this strategy to pyridinylimidazole-based covalent JNK3 inhibitors, we used acrylamido-N-(4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)phenyl)benzamide (1) as a lead compound to design novel covalent inhibitors of JNK3 by modifying the amide bond moiety in the linker. The newly synthesized inhibitors demonstrated IC50 values in the low double-digit nanomolar range in a radiometric kinase assay. They were further characterized in a NanoBRETTM intracellular JNK3 assay, where covalent engagement of the target enzyme was confirmed by compound washout experiments and a loss in binding affinity for a newly generated JNK3(C154A)-NLuc mutant. The most potent compound of the series, N-(3-acrylamidophenyl)-4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)benzamide (13), was equipped with a photolabile protecting group leading to a nearly 10-fold decrease in intracellular JNK3 binding affinity, which was fully recovered by UV irradiation at a wavelength of 365 nm within 8 min. Our results highlight that photocaged covalent inhibitors can serve as a pharmacological tool to control JNK3 activity in live cells with light. Full article
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24 pages, 8435 KiB  
Article
Discovery of Polyphenolic Natural Products as SARS-CoV-2 Mpro Inhibitors for COVID-19
by Nadine Krüger, Thales Kronenberger, Hang Xie, Cheila Rocha, Stefan Pöhlmann, Haixia Su, Yechun Xu, Stefan A. Laufer and Thanigaimalai Pillaiyar
Pharmaceuticals 2023, 16(2), 190; https://doi.org/10.3390/ph16020190 - 28 Jan 2023
Cited by 14 | Viewed by 2985
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has forced the development of direct-acting antiviral drugs due to the coronavirus disease 2019 (COVID-19) pandemic. The main protease of SARS-CoV-2 is a crucial enzyme that breaks down polyproteins synthesized from the viral RNA, making [...] Read more.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has forced the development of direct-acting antiviral drugs due to the coronavirus disease 2019 (COVID-19) pandemic. The main protease of SARS-CoV-2 is a crucial enzyme that breaks down polyproteins synthesized from the viral RNA, making it a validated target for the development of SARS-CoV-2 therapeutics. New chemical phenotypes are frequently discovered in natural goods. In the current study, we used a fluorogenic assay to test a variety of natural products for their ability to inhibit SARS-CoV-2 Mpro. Several compounds were discovered to inhibit Mpro at low micromolar concentrations. It was possible to crystallize robinetin together with SARS-CoV-2 Mpro, and the X-ray structure revealed covalent interaction with the protease’s catalytic Cys145 site. Selected potent molecules also exhibited antiviral properties without cytotoxicity. Some of these powerful inhibitors might be utilized as lead compounds for future COVID-19 research. Full article
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13 pages, 2800 KiB  
Article
BIreactive: Expanding the Scope of Reactivity Predictions to Propynamides
by Markus R. Hermann, Christofer S. Tautermann, Peter Sieger, Marc A. Grundl and Alexander Weber
Pharmaceuticals 2023, 16(1), 116; https://doi.org/10.3390/ph16010116 - 12 Jan 2023
Cited by 3 | Viewed by 2354
Abstract
We present the first comprehensive study on the prediction of reactivity for propynamides. Covalent inhibitors like propynamides often show improved potency, selectivity, and unique pharmacologic properties compared to their non-covalent counterparts. In order to achieve this, it is essential to tune the reactivity [...] Read more.
We present the first comprehensive study on the prediction of reactivity for propynamides. Covalent inhibitors like propynamides often show improved potency, selectivity, and unique pharmacologic properties compared to their non-covalent counterparts. In order to achieve this, it is essential to tune the reactivity of the warhead. This study shows how three different in silico methods can predict the in vitro properties of propynamides, a covalent warhead class integrated into approved drugs on the market. Whereas the electrophilicity index is only applicable to individual subclasses of substitutions, adduct formation and transition state energies have a good predictability for the in vitro reactivity with glutathione (GSH). In summary, the reported methods are well suited to estimate the reactivity of propynamides. With this knowledge, the fine tuning of the reactivity is possible which leads to a speed up of the design process of covalent drugs. Full article
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Review

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40 pages, 14013 KiB  
Review
Covalent Inhibitors for Neglected Diseases: An Exploration of Novel Therapeutic Options
by Erick Tavares Marcelino Alves, Filipe Gomes Pernichelle, Lucas Adriano Nascimento, Glaucio Monteiro Ferreira and Elizabeth Igne Ferreira
Pharmaceuticals 2023, 16(7), 1028; https://doi.org/10.3390/ph16071028 - 19 Jul 2023
Cited by 3 | Viewed by 2346
Abstract
Neglected diseases, primarily found in tropical regions of the world, present a significant challenge for impoverished populations. Currently, there are 20 diseases considered neglected, which greatly impact the health of affected populations and result in difficult-to-control social and economic consequences. Unfortunately, for the [...] Read more.
Neglected diseases, primarily found in tropical regions of the world, present a significant challenge for impoverished populations. Currently, there are 20 diseases considered neglected, which greatly impact the health of affected populations and result in difficult-to-control social and economic consequences. Unfortunately, for the majority of these diseases, there are few or no drugs available for patient treatment, and the few drugs that do exist often lack adequate safety and efficacy. As a result, there is a pressing need to discover and design new drugs to address these neglected diseases. This requires the identification of different targets and interactions to be studied. In recent years, there has been a growing focus on studying enzyme covalent inhibitors as a potential treatment for neglected diseases. In this review, we will explore examples of how these inhibitors have been used to target Human African Trypanosomiasis, Chagas disease, and Malaria, highlighting some of the most promising results so far. Ultimately, this review aims to inspire medicinal chemists to pursue the development of new drug candidates for these neglected diseases, and to encourage greater investment in research in this area. Full article
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33 pages, 7233 KiB  
Review
Recent Advances in Covalent Drug Discovery
by Daniel Schaefer and Xinlai Cheng
Pharmaceuticals 2023, 16(5), 663; https://doi.org/10.3390/ph16050663 - 28 Apr 2023
Cited by 24 | Viewed by 8619
Abstract
In spite of the increasing number of biologics license applications, the development of covalent inhibitors is still a growing field within drug discovery. The successful approval of some covalent protein kinase inhibitors, such as ibrutinib (BTK covalent inhibitor) and dacomitinib (EGFR covalent inhibitor), [...] Read more.
In spite of the increasing number of biologics license applications, the development of covalent inhibitors is still a growing field within drug discovery. The successful approval of some covalent protein kinase inhibitors, such as ibrutinib (BTK covalent inhibitor) and dacomitinib (EGFR covalent inhibitor), and the very recent discovery of covalent inhibitors for viral proteases, such as boceprevir, narlaprevir, and nirmatrelvir, represent a new milestone in covalent drug development. Generally, the formation of covalent bonds that target proteins can offer drugs diverse advantages in terms of target selectivity, drug resistance, and administration concentration. The most important factor for covalent inhibitors is the electrophile (warhead), which dictates selectivity, reactivity, and the type of protein binding (i.e., reversible or irreversible) and can be modified/optimized through rational designs. Furthermore, covalent inhibitors are becoming more and more common in proteolysis, targeting chimeras (PROTACs) for degrading proteins, including those that are currently considered to be ‘undruggable’. The aim of this review is to highlight the current state of covalent inhibitor development, including a short historical overview and some examples of applications of PROTAC technologies and treatment of the SARS-CoV-2 virus. Full article
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46 pages, 24845 KiB  
Review
Technologies for Direct Detection of Covalent Protein–Drug Adducts
by Elma Mons, Robbert Q. Kim and Monique P. C. Mulder
Pharmaceuticals 2023, 16(4), 547; https://doi.org/10.3390/ph16040547 - 5 Apr 2023
Cited by 9 | Viewed by 6725
Abstract
In the past two decades, drug candidates with a covalent binding mode have gained the interest of medicinal chemists, as several covalent anticancer drugs have successfully reached the clinic. As a covalent binding mode changes the relevant parameters to rank inhibitor potency and [...] Read more.
In the past two decades, drug candidates with a covalent binding mode have gained the interest of medicinal chemists, as several covalent anticancer drugs have successfully reached the clinic. As a covalent binding mode changes the relevant parameters to rank inhibitor potency and investigate structure-activity relationship (SAR), it is important to gather experimental evidence on the existence of a covalent protein–drug adduct. In this work, we review established methods and technologies for the direct detection of a covalent protein–drug adduct, illustrated with examples from (recent) drug development endeavors. These technologies include subjecting covalent drug candidates to mass spectrometric (MS) analysis, protein crystallography, or monitoring intrinsic spectroscopic properties of the ligand upon covalent adduct formation. Alternatively, chemical modification of the covalent ligand is required to detect covalent adducts by NMR analysis or activity-based protein profiling (ABPP). Some techniques are more informative than others and can also elucidate the modified amino acid residue or bond layout. We will discuss the compatibility of these techniques with reversible covalent binding modes and the possibilities to evaluate reversibility or obtain kinetic parameters. Finally, we expand upon current challenges and future applications. Overall, these analytical techniques present an integral part of covalent drug development in this exciting new era of drug discovery. Full article
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19 pages, 7524 KiB  
Review
Extended Applications of Small-Molecule Covalent Inhibitors toward Novel Therapeutic Targets
by Jesang Lee and Seung Bum Park
Pharmaceuticals 2022, 15(12), 1478; https://doi.org/10.3390/ph15121478 - 27 Nov 2022
Cited by 1 | Viewed by 6033
Abstract
Recently, small-molecule covalent inhibitors have been accepted as a practical tool for targeting previously “undruggable” proteins. The high target selectivity of modern covalent inhibitors is now alleviating toxicity concerns regarding the covalent modifications of proteins. However, despite the tremendous clinical success of current [...] Read more.
Recently, small-molecule covalent inhibitors have been accepted as a practical tool for targeting previously “undruggable” proteins. The high target selectivity of modern covalent inhibitors is now alleviating toxicity concerns regarding the covalent modifications of proteins. However, despite the tremendous clinical success of current covalent inhibitors, there are still unmet medical needs that covalent inhibitors have not yet addressed. This review categorized representative covalent inhibitors based on their mechanism of covalent inhibition: conventional covalent inhibitors, targeted covalent inhibitors (TCIs), and expanded TCIs. By reviewing both Food and Drug Administration (FDA)-approved drugs and drug candidates from recent literature, we provide insight into the future direction of covalent inhibitor development. Full article
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22 pages, 1485 KiB  
Review
Reactivity of Covalent Fragments and Their Role in Fragment Based Drug Discovery
by Kirsten McAulay, Alan Bilsland and Marta Bon
Pharmaceuticals 2022, 15(11), 1366; https://doi.org/10.3390/ph15111366 - 8 Nov 2022
Cited by 16 | Viewed by 7998
Abstract
Fragment based drug discovery has long been used for the identification of new ligands and interest in targeted covalent inhibitors has continued to grow in recent years, with high profile drugs such as osimertinib and sotorasib gaining FDA approval. It is therefore unsurprising [...] Read more.
Fragment based drug discovery has long been used for the identification of new ligands and interest in targeted covalent inhibitors has continued to grow in recent years, with high profile drugs such as osimertinib and sotorasib gaining FDA approval. It is therefore unsurprising that covalent fragment-based approaches have become popular and have recently led to the identification of novel targets and binding sites, as well as ligands for targets previously thought to be ‘undruggable’. Understanding the properties of such covalent fragments is important, and characterizing and/or predicting reactivity can be highly useful. This review aims to discuss the requirements for an electrophilic fragment library and the importance of differing warhead reactivity. Successful case studies from the world of drug discovery are then be examined. Full article
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11 pages, 2624 KiB  
Review
Systematic Exploration of Privileged Warheads for Covalent Kinase Drug Discovery
by Zheng Zhao and Philip E. Bourne
Pharmaceuticals 2022, 15(11), 1322; https://doi.org/10.3390/ph15111322 - 26 Oct 2022
Cited by 7 | Viewed by 3618
Abstract
Kinase-targeted drug discovery for cancer therapy has advanced significantly in the last three decades. Currently, diverse kinase inhibitors or degraders have been reported, such as allosteric inhibitors, covalent inhibitors, macrocyclic inhibitors, and PROTAC degraders. Out of these, covalent kinase inhibitors (CKIs) have been [...] Read more.
Kinase-targeted drug discovery for cancer therapy has advanced significantly in the last three decades. Currently, diverse kinase inhibitors or degraders have been reported, such as allosteric inhibitors, covalent inhibitors, macrocyclic inhibitors, and PROTAC degraders. Out of these, covalent kinase inhibitors (CKIs) have been attracting attention due to their enhanced selectivity and exceptionally strong affinity. Eight covalent kinase drugs have been FDA-approved thus far. Here, we review current developments in CKIs. We explore the characteristics of the CKIs: the features of nucleophilic amino acids and the preferences of electrophilic warheads. We provide systematic insights into privileged warheads for repurposing to other kinase targets. Finally, we discuss trends in CKI development across the whole proteome. Full article
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