Journal ArticleDOI
Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology
Matthias Gehringer,Stefan Laufer +1 more
TLDR
An overview of warheads-beyond α,β-unsaturated amides-recently used in the design of targeted covalent ligands is provided, with special emphasis on the discussion of reactivity and of case studies illustrating applications in medicinal chemistry and chemical biology.Abstract:
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 the predominant strategy in TCI development. The recent ascent of covalent drugs has stimulated considerable efforts to characterize alternative warheads for the covalent-reversible and irreversible engagement of noncatalytic cysteine residues as well as other amino acids. This Perspective article provides an overview of warheads—beyond α,β-unsaturated amides—recently used in the design of targeted covalent ligands. Promising reactive groups that have not yet demonstrated their utility in TCI development are also highlighted. Special emphasis is placed on the discussion of reactivity and of case studies illustrating applications in medicinal chemistry and chemical biology.read more
Citations
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Journal ArticleDOI
RAS-targeted therapies: is the undruggable drugged?
TL;DR: How drugs that target RAS or associated pathways might be used effectively, particularly in combinations, are explored, and other RAS-targeted therapies in the pipeline are discussed, including combination strategies.
Journal ArticleDOI
PROTACs: An Emerging Therapeutic Modality in Precision Medicine.
TL;DR: This review highlights the key advantages of PROTACs and then discusses the spatiotemporal regulation of protein degradation, and explores current chemically tractable E3 ligases focusing on expanding the existing repertoire with novel E3ligases to uncover the full potential of TPD.
Journal ArticleDOI
Covalent inhibitors: A rational approach to drug discovery
TL;DR: In this review, a brief historic overview of covalent inhibitors is provided and recent advances focusing on developments in the last decade are summarized.
Journal ArticleDOI
Spirocyclic Scaffolds in Medicinal Chemistry.
TL;DR: In this article, the authors summarize the diverse synthetic routes to obtain spirocyclic systems and the impact of spirocycles on potency and selectivity, including the aspect of stereochemistry.
Journal ArticleDOI
Advances in covalent kinase inhibitors.
TL;DR: A comprehensive overview of covalent kinase inhibitors reported in the literature over a decade period, 2007-2018 is provided, with emphasis on the rationale behind warhead choice, optimization approach, and inhibitor design.
References
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DrugBank 5.0: a major update to the DrugBank database for 2018
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How to improve R&D productivity: the pharmaceutical industry's grand challenge
Steven M. Paul,Daniel S. Mytelka,Dunwiddie Christopher T,Charles C. Persinger,Bernard H. Munos,Stacy R. Lindborg,Aaron Leigh Schacht +6 more
TL;DR: A detailed analysis based on comprehensive, recent, industry-wide data is presented to identify the relative contributions of each of the steps in the drug discovery and development process to overall R&D productivity and propose specific strategies that could have the most substantial impact in improving R &D productivity.
Journal ArticleDOI
Applications of Fluorine in Medicinal Chemistry
TL;DR: The effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography are provided, as well as new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds.
Journal ArticleDOI
Proteomic analysis of post-translational modifications.
Matthias Mann,Ole N. Jensen +1 more
TL;DR: Stable isotope labeling strategies in combination with mass spectrometry have been applied successfully to study the dynamics of modifications and hold tremendous potential to map modification sites in molecular detail.