Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology.

@article{Gehringer2019EmergingAR,
  title={Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology.},
  author={Matthias Gehringer and Stefan A. Laufer},
  journal={Journal of medicinal chemistry},
  year={2019}
}
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… 

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References

SHOWING 1-10 OF 305 REFERENCES

Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain.

The first reversible covalent inhibitors for Mcl-1, a protein-protein interaction (PPI) target that has proven difficult to inhibit via traditional medicinal chemistry strategies, are generated using aryl boronic acid carbonyl warheads to covalently target a noncatalytic lysine side chain.

Expanding the Armory: Predicting and Tuning Covalent Warhead Reactivity.

The ability of several experimental and computational approaches to predict GSH t1/2 for a range of cysteine targeting warheads is assessed, including a novel method based on pKa and matched molecular pairs analysis has been performed against the internal compound collection, revealing structure-activity relationships between a selection of different covalent warheads.

The Cysteinome of Protein Kinases as a Target in Drug Development.

Recent developments of this rapidly growing area in kinase drug development are reviewed and the unique opportunities and challenges of this strategy are highlighted.

Identification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent Inhibitors.

It was demonstrated that selective inhibition of JAK3 is sufficient to drive JAK1/JAK3-mediated cellular responses and gave key insights into a productive approach to decrease glutathione/glutathione S-transferase-mediated clearance, a challenge typically encountered during the discovery of covalent kinase inhibitors.

Targeted Covalent Inhibitors for Drug Design.

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.

Chemical and computational methods for the characterization of covalent reactive groups for the prospective design of irreversible inhibitors.

Methods for measuring the reactivity of covalent reactive groups (CRGs) with a biologically relevant nucleophile, glutathione (GSH), along with kinetic data for a broad array of electrophiles are described.

2-Chloropropionamide As a Low-Reactivity Electrophile for Irreversible Small-Molecule Probe Identification.

A novel PDI inhibitor highlights the potential of 2-chloropropionamides as weak and stereochemically tunable electrophiles for covalent drug discovery.

Electrophilic fragment-based design of reversible covalent kinase inhibitors.

This work identifies electrophilic fragments with sufficient ligand efficiency and selectivity to serve as starting points for the first reported inhibitors of the MSK1 C-terminal kinase domain using a panel of low-molecular-weight, heteroaryl-susbstituted cyanoacrylamides, which have been shown to form reversible covalent bonds with cysteine thiols.

Diverse Redoxome Reactivity Profiles of Carbon Nucleophiles.

A novel library of diverse carbon-based nucleophile fragments that react selectively with cysteine sulfenic acid formed in proteins via oxidation or hydrolysis reactions is developed, offering new chemical tools to investigate redox-regulation of protein function.
...