STEFs: Activated Vinylogous Protein‐Reactive Electrophiles

Hansen, Bente K.; Loveridge, Christopher J.; Thyssen, Stine; Wørmer, Gustav J.; Nielsen, Andreas D.; Palmfeldt, Johan; Johannsen, Mogens; Poulsen, Thomas B.

doi:10.1002/ange.201814073

Cited by 12 publications

(10 citation statements)

References 30 publications

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“…(B) Example compounds developed using DNA-encoded chemical libraries that target JNK1 (Zimmermann et al, 2017) and ERBB2 (Zambaldo et al, 2016). (C) b-Heteroatom substituted acrylamides warheads STEFs and their mechanism (Hansen et al, 2019). (D) Terminal alkyne as a warhead, included here into a potent cathepsin K (CatK) inhibitor, odanacatib (Mons et al, 2019).…”

Section: Discovery Of Novel Warheadsmentioning

confidence: 99%

“…SFs and spiroepoxides, are reactive toward multiple side chains, and selectivity mapping studies need to address not only the range of targets but the range of nucleophilic sites on proteins that a given warhead reacts with, as discussed in a recent perspective (Gehringer and Laufer, 2019). Here, we would like to comment on two warheads reported in the short time since the publication of that perspective, semi-oxamide vinylogous thioesters (Hansen et al, 2019) and alkynes (Mons et al, 2019). Hansen et al use b-heteroatom-substituted acrylamides as a starting point for developing a class of electrophiles that reacts via an addition-elimination reaction named STEFs (Figure 6C).…”

Section: Discovery Of Novel Warheadsmentioning

confidence: 99%

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Recent Advances in Selective and Irreversible Covalent Ligand Development and Validation

Zhang

Hatcher

Teng

et al. 2019

Cell Chemical Biology

136

128

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Some of the most widely used drugs, such as aspirin and penicillin, are covalent drugs. Covalent binding can improve potency, selectivity, and duration of the effects, but the intrinsic reactivity represents a potential liability and may result in idiosyncratic toxicity. For decades, the cons were believed to outweigh the pros, and covalent targeting was deprioritized in drug discovery. Recently, several covalent inhibitors have been approved for cancer treatment, thus rebooting the field. In this review, we briefly reflect on the history of selective covalent targeting, and provide a comprehensive overview of emerging developments from a chemical biology stand-point. Our discussion will reflect on efforts to validate irreversible covalent ligands, expand the scope of targets, and discover new ligands and warheads. We conclude with a brief commentary of remaining limitations and emerging opportunities in selective covalent targeting.

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Section: Discovery Of Novel Warheadsmentioning

confidence: 99%

Section: Discovery Of Novel Warheadsmentioning

confidence: 99%

Recent Advances in Selective and Irreversible Covalent Ligand Development and Validation

Zhang

Hatcher

Teng

et al. 2019

Cell Chemical Biology

136

128

View full text Add to dashboard Cite

show abstract

“…1B). 35 The STEF reagents are modified vinylogous thioesters that enable irreversible conjugation to lysine residues via a proximal cysteine having undergone initial, fast thiolexchange with the STEF-reagent (Fig. 1B).…”

Section: Introductionmentioning

confidence: 99%

oxSTEF reagents are tunable and versatile electrophiles for selective disulfide-rebridging of native proteins

Nišavić

Wørmer

Nielsen

et al. 2022

Preprint

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Site-selective disulfide rebridging has emerged as a powerful strategy to modulate structural and functional properties of proteins. Here, we introduce a novel class of electrophilic reagents, designated oxSTEF, that demonstrate excellent efficiency in disulfide rebridging via double thiol-exchange. The oxSTEF reagents are prepared using an efficient synthetic sequence which may be diverted to obtain a range of structural derivatives. We demonstrate highly selective rebridging of cyclic peptides and native proteins, such as human growth hormone, and absence of cross-reactivity with other nucleophilic amino acid residues. The oxSTEF-conjugates undergo glutathione-mediated disintegration under tumor relevant glutathione concentrations, which highlights the potential for use in targeted drug delivery. Finally, the α-dicarbonyl motif of the oxSTEF reagents enables “second phase” oxime ligation which furthermore increases the thiol-stability of the conjugates significantly.

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“…4,[11][12][13] As a separate area of application, many bioconjugation methods also rely on electrophilic agents with the aim of achieving selective biomolecular labelling with residue-or sequence-specific resolution. The introduction of new electrophilic motifs can therefore have broad impact and this is an area that we, 14,15 as well as many others, [16][17][18][19][20][21][22][23] have been recently pursuing.…”

Section: Introductionmentioning

confidence: 99%

A stable α-lactam reagent for bioconjugation and proteomic profiling

Mahía

Kiib

Nišavić

et al. 2022

Preprint

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Electrophilic groups are one of the key pillars of contemporary chemical biology and medicinal chemistry, constituting the anchor point for the design of targeted covalent inhibitors, the identification of novel therapeutic targets, and the development of a wide diversity of bioconjugation and proteomic profiling techniques. Naturally, there is great interest in the discovery of new types of biologically relevant electrophiles with potent action and broad applicability. For instance, the group of 3-membered N-heterocyclic compounds - such as aziridines, azirines, and oxaziridines – combine unique electronic properties and structural strain to trigger their respective potential and applicability as covalent tools. The α-lactams are also members of this group of compounds, but, until this point, their utility within the field has been unexplored. Here, we demonstrate an α-lactam reagent that can be efficiently employed in the framework of bioconjugation and proteomic profiling. We have designed and synthesised a stable α-lactam, AM2, that is compatible with aqueous buffers, and have extensively characterised its properties and reactivity. In simple settings, AM2 was e.g. found to be reactive towards both thiols and amines, with the former reacting significantly faster. We further demonstrated that AM2 undergoes conjugation to free cysteine residues in peptides suggesting applications for bioconjugation. Interestingly, liver carboxylesterase 1 (CES1), a serine hydrolase with key roles in both endo- and xenobiotic metabolism, was found as a highly selective covalent target for AM2 in HepG2 liver cancer cells. All in all, our study constitutes the starting point for the further development of α-lactam-based electrophilic probes and exploration of their use in covalent chemical biology.

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STEFs: Activated Vinylogous Protein‐Reactive Electrophiles

Cited by 12 publications

References 30 publications

Recent Advances in Selective and Irreversible Covalent Ligand Development and Validation

Recent Advances in Selective and Irreversible Covalent Ligand Development and Validation

oxSTEF reagents are tunable and versatile electrophiles for selective disulfide-rebridging of native proteins

A stable α-lactam reagent for bioconjugation and proteomic profiling

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