Drug discovery for a new generation of covalent drugs
TL;DR: The review examines potential reason(s) for the excellent safety record of marketed covalent agents and advanced clinical candidates for emerging therapeutic targets and significant emphasis is placed on proteomic techniques and chemical/biochemical reactivity assays that aim to provide a systematic rank ordering of pharmacologic selectivity relative to off-target protein reactivity of covalents.
Abstract: Introduction: The design of target-specific covalent inhibitors is conceptually attractive because of increased biochemical efficiency through covalency and increased duration of action that outlasts the pharmacokinetics of the agent. Although many covalent inhibitors have been approved or are in advanced clinical trials to treat indications such as cancer and hepatitis C, there is a general tendency to avoid them as drug candidates because of concerns regarding immune-mediated toxicity that can arise from indiscriminate reactivity with off-target proteins. Areas covered: The review examines potential reason(s) for the excellent safety record of marketed covalent agents and advanced clinical candidates for emerging therapeutic targets. A significant emphasis is placed on proteomic techniques and chemical/biochemical reactivity assays that aim to provide a systematic rank ordering of pharmacologic selectivity relative to off-target protein reactivity of covalent inhibitors. Expert opinion: While tactics to...
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TL;DR: Evidence is provided that curcumin is an unstable, reactive, nonbioavailable compound and, therefore, a highly improbable lead and, on the basis of this in-depth evaluation, potential new directions for research onCurcuminoids are discussed.
Abstract: Curcumin is a constituent (up to ∼5%) of the traditional medicine known as turmeric. Interest in the therapeutic use of turmeric and the relative ease of isolation of curcuminoids has led to their extensive investigation. Curcumin has recently been classified as both a PAINS (pan-assay interference compounds) and an IMPS (invalid metabolic panaceas) candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clinical trials of curcuminoids against several diseases. No double-blinded, placebo controlled clinical trial of curcumin has been successful. This manuscript reviews the essential medicinal chemistry of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compound and, therefore, a highly improbable lead. On the basis of this in-depth evaluation, potential new directions for research on curcuminoids are discussed.
1,191 citations
TL;DR: Evidence suggests that there is a reduced risk for the development of resistance against covalent drugs, which is a major challenge in areas such as oncology and infectious disease.
385 citations
TL;DR: The covalent inhibitor approach is rapidly gaining acceptance as a valuable tool in drug discovery, and is poised to make a major impact on the design of enzyme inhibitors and receptor modulators.
Abstract: In contrast to the traditional mechanism of drug action that relies on the reversible, noncovalent interaction of a ligand with its biological target, a targeted covalent inhibitor (TCI) is designed such that the initial, reversible association is followed by the formation of a covalent bond between an electrophile on the ligand and a nucleophilic center in the protein. Although this approach offers a variety of potential benefits (high potency and extended duration of action), concerns over the possible toxicological consequences of protein haptenization have hindered the development of the TCI concept. Recently, approaches to mitigate the risk of serious adverse reactions to this new class of agent have emerged, thus stimulating interest in the field and leading to authorization of the first cadre of TCIs to be marketed. The covalent inhibitor approach is rapidly gaining acceptance as a valuable tool in drug discovery, and is poised to make a major impact on the design of enzyme inhibitors and receptor modulators.
341 citations
TL;DR: This Perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors.
Abstract: Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogues possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This Perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This Perspective is focused on α,β-unsaturated carbonyls given their preponderance in bioactive ...
322 citations
TL;DR: Progress is demonstrated by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors to discover potent and selective BTK inhibitors that demonstrate biochemical residence times spanning from minutes to 7 days.
Abstract: Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo.
299 citations
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TL;DR: The survey results support the value of in vivo toxicology studies to predict for many significant HTs associated with pharmaceuticals and have helped to identify HT categories that may benefit from improved methods.
1,699 citations
Journal Article•
TL;DR: A fundamental role of glutathione in the body may be to protect tissues against electrophilic attack by drug metabolites and other alkylating agents.
Abstract: The possibility that glutathione may protect against acetaminophen-induced hepatic necrosis was examined. Pretreatment of mice with diethyl maleate, which depletes hepatic glutathione, potentiated acetaminophen-induced hepatic necrosis, whereas pretreatment with cysteine, a glutathione precursor, prevented hepatic damage. Administration of acetaminophen caused a dose-dependent depletion of hepatic glutathione. Glutathione depletion by acetaminophen was enhanced by treatments that potentiate the hepatic necrosis and covalent binding produced by the toxic metabolite of acetaminophen. Conversely, glutathione depletion was inhibited by treatments that protect against these toxic effects. Moreover, covalent binding of this metabolite to hepatic macromolecules did not occur until the availability of glutathione was exhausted through conjugation with the metabolite. Similarly, alteration of glutathione availability by pretreatment with diethyl maleate or cysteine, respectively, increased or decreased covalent binding of the toxic metabolite. We propose that. a fundamental role of glutathione in the body may be to protect tissues against electrophilic attack by drug metabolites and other alkylating agents.
1,666 citations
TL;DR: The relationship between the metabolic disposition of acetaminophen and the susceptibility of hamsters, mice and rats toacetaminophen-induced liver necrosis has been examined.
Abstract: The relationship between the metabolic disposition of acetaminophen and the susceptibility of hamsters, mice and rats to acetaminophen-induced liver necrosis has been examined. The fraction of low dos
1,383 citations
TL;DR: The prevalence and pharmacological advantages of covalent drugs are surveyed, how potential risks and challenges may be addressed through innovative design, and the broad opportunities provided by targeted covalENT inhibitors are presented.
Abstract: Covalent drugs have proved to be successful therapies for various indications, but largely owing to safety concerns, they are rarely considered when initiating a target-directed drug discovery project. There is a need to reassess this important class of drugs, and to reconcile the discordance between the historic success of covalent drugs and the reluctance of most drug discovery teams to include them in their armamentarium. This review surveys the prevalence and pharmacological advantages of covalent drugs, discusses how potential risks and challenges may be addressed through innovative design, and presents the broad opportunities provided by targeted covalent inhibitors.
1,363 citations
TL;DR: It is demonstrated that quantitative reactivity profiling can form the basis for screening and functional assignment of cysteines in computationally designed proteins, where it discriminated catalytically active from inactive cysteine hydrolase designs.
Abstract: Cysteine is the most intrinsically nucleophilic amino acid in proteins, where its reactivity is tuned to perform diverse biochemical functions The absence of a consensus sequence that defines functional cysteines in proteins has hindered their discovery and characterization Here we describe a proteomics method to profile quantitatively the intrinsic reactivity of cysteine residues en masse directly in native biological systems Hyper-reactivity was a rare feature among cysteines and it was found to specify a wide range of activities, including nucleophilic and reductive catalysis and sites of oxidative modification Hyper-reactive cysteines were identified in several proteins of uncharacterized function, including a residue conserved across eukaryotic phylogeny that we show is required for yeast viability and is involved in iron-sulphur protein biogenesis We also demonstrate that quantitative reactivity profiling can form the basis for screening and functional assignment of cysteines in computationally designed proteins, where it discriminated catalytically active from inactive cysteine hydrolase designs
1,295 citations