Editorial

4 pages, 177 KiB

Open AccessEditorial

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://0-doi-org.brum.beds.ac.uk/10.3390/ph17020206 - 05 Feb 2024

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Covalent inhibitors have experienced a revival in medicinal chemistry and chemical biology in recent decades [...] Full article

(This article belongs to the Special Issue Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond)

Research

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17 pages, 5154 KiB

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/ph16020264 - 09 Feb 2023

Cited by 1 | Viewed by 1804

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 NanoBRET^TM 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

(This article belongs to the Special Issue Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond)

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24 pages, 8435 KiB

Open AccessArticle

Discovery of Polyphenolic Natural Products as SARS-CoV-2 M^pro 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://0-doi-org.brum.beds.ac.uk/10.3390/ph16020190 - 28 Jan 2023

Cited by 10 | Viewed by 2296

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 M^pro. Several compounds were discovered to inhibit M^pro at low micromolar concentrations. It was possible to crystallize robinetin together with SARS-CoV-2 M^pro, 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

(This article belongs to the Special Issue Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond)

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13 pages, 2800 KiB

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/ph16010116 - 12 Jan 2023

Cited by 2 | Viewed by 1918

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

(This article belongs to the Special Issue Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond)

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Review

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40 pages, 14013 KiB

Open AccessReview

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://0-doi-org.brum.beds.ac.uk/10.3390/ph16071028 - 19 Jul 2023

Viewed by 1744

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

(This article belongs to the Special Issue Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond)

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33 pages, 7233 KiB

Open AccessReview

Recent Advances in Covalent Drug Discovery

by Daniel Schaefer and Xinlai Cheng

Pharmaceuticals 2023, 16(5), 663; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16050663 - 28 Apr 2023

Cited by 12 | Viewed by 5575

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

(This article belongs to the Special Issue Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond)

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46 pages, 24845 KiB

Open AccessEditor’s ChoiceReview

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://0-doi-org.brum.beds.ac.uk/10.3390/ph16040547 - 05 Apr 2023

Cited by 5 | Viewed by 5088

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

(This article belongs to the Special Issue Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond)

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19 pages, 7524 KiB

Open AccessFeature PaperReview

Extended Applications of Small-Molecule Covalent Inhibitors toward Novel Therapeutic Targets

by Jesang Lee and Seung Bum Park

Pharmaceuticals 2022, 15(12), 1478; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15121478 - 27 Nov 2022

Cited by 1 | Viewed by 4539

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

(This article belongs to the Special Issue Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond)

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22 pages, 1485 KiB

Open AccessEditor’s ChoiceReview

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://0-doi-org.brum.beds.ac.uk/10.3390/ph15111366 - 08 Nov 2022

Cited by 14 | Viewed by 5638

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

(This article belongs to the Special Issue Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond)

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11 pages, 2624 KiB

Open AccessReview

Systematic Exploration of Privileged Warheads for Covalent Kinase Drug Discovery

by Zheng Zhao and Philip E. Bourne

Pharmaceuticals 2022, 15(11), 1322; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15111322 - 26 Oct 2022

Cited by 4 | Viewed by 2928

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

(This article belongs to the Special Issue Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond)

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