Intrinsic reactivity profile of electrophilic moieties to guide covalent drug design: N-α-acetyl-<scp>l</scp>-lysine as an amine nucleophile

Dahal, Upendra P.; Gilbert, Adam M.; Obach, R. Scott; Flanagan, Mark E.; Chen, Jinshan M.; García-Irizarry, Carmen N.; Starr, Jeremy T.; Schuff, Brandon P.; Uccello, Daniel P.; Young, Jennifer A.

doi:10.1039/c6md00017g

Cited by 50 publications

(46 citation statements)

References 29 publications

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“…12 Covalent conjugation with lysine is far less common, due to its protonation state, and therefore poorer nucleophilicity under physiological conditions. 13 Nonetheless, interest in this nucleophile is rapidly gaining traction in the scientific community. [14][15][16][17][18] The heterodimeric lipid kinase phosphoinositide 3kinase delta (PI3Kδ) 19,20 has been targeted specifically over the related PI3Kα, β and γ isoforms for the treatment of a variety of diseases.…”

Section: Introductionmentioning

confidence: 99%

Selectively Targeting the Kinome-Conserved Lysine of PI3Kδ as a General Approach to Covalent Kinase Inhibition

Dittus²,

et al. 2018

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Selective covalent inhibition of kinases by targeting poorly conserved cysteines has proven highly fruitful to date in the development of chemical probes and approved drugs. However, this approach is limited to ∼200 kinases possessing such a cysteine near the ATP-binding pocket. Herein, we report a novel approach to achieve selective, irreversible kinase inhibition, by targeting the conserved catalytic lysine residue. We have illustrated our approach by developing selective, covalent PI3Kδ inhibitors that exhibit nanomolar potency in cellular assays, and a duration of action >48 h in CD4+ T cells. Despite conservation of the lysine residue throughout the kinome, the lead compound shows high levels of selectivity over a selection of lipid and protein kinases in biochemical assays, as well as covalent binding to very few off-target proteins in live-cell proteomic studies. We anticipate this approach could offer a general strategy, as an alternative to targeting non-conserved cysteines, for the development of selective covalent kinase inhibitors.

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Section: Introductionmentioning

confidence: 99%

Selectively Targeting the Kinome-Conserved Lysine of PI3Kδ as a General Approach to Covalent Kinase Inhibition

Dittus²,

et al. 2018

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“…To evaluate the intrinsic reactivity profile of lysine,Dahal et al experimentally determined its rate of reaction with various electrophiles suitable for use as irreversible inhibitor warheads (Table 1). [34] Their study used N-a-acetyl-lysine as an ucleophile,s ot oaccount for the hypothetical perturbed pK a of al ysine residue in ap rotein microenvironment, the reactivity was assessed at pH 10.2. Ther elative rates were compared with the soft thiol nucleophile glutathione (GSH).…”

Section: Hard and Soft Electrophilesmentioning

confidence: 99%

Lysine‐Targeting Covalent Inhibitors

2017

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Targeted covalent inhibitors have gained widespread attention in drug discovery as a validated method to circumvent acquired resistance in oncology. This strategy exploits small-molecule/protein crystal structures to design tightly binding ligands with appropriately positioned electrophilic warheads. Whilst most focus has been on targeting binding-site cysteine residues, targeting nucleophilic lysine residues can also represent a viable approach to irreversible inhibition. However, owing to the basicity of the ϵ-amino group in lysine, this strategy generates a number of specific challenges. Herein, we review the key principles for inhibitor design, give historical examples, and present recent developments that demonstrate the potential of lysine targeting for future drug discovery.

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“…Dahal et al. untersuchten das intrinsische Reaktivitätsprofil von Lysin, indem sie seine Reaktionsgeschwindigkeit mit verschiedenen Elektrophilen, die sich als irreversible Inhibitor‐Gefechtsköpfe eigneten, experimentell bestimmten (Tabelle ) . Die Verwendung von N ‐α‐Acetyllysin als Nukleophil berücksichtigte den hypothetisch gestörten p K a ‐Wert eines Lysinrests in einer Proteinmikroumgebung, und die Reaktivität wurde bei pH 10.2 bestimmt.…”

Section: Harte Und Weiche Elektrophileunclassified

Auf Lysin zielende, kovalente Inhibitoren

2017

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Zielgerichtete kovalente Inhibitoren haben in der Wirkstoffentwicklung breite Beachtung gefunden, da sie in der Onkologie eine validierte Methode zur Verhinderung erworbener Resistenzen bieten. Dabei werden die Kristallstrukturen der Komplexe von Proteinen mit niedermolekularen Verbindungen verwendet, um fest bindende Liganden mit passend positionierten elektrophilen Gefechtsköpfen (“warheads”) zu entwickeln. Der Schwerpunkt liegt zwar auf Cysteinresten als Bindungsstellen, aber auch nukleophile Lysinreste können einen Zugang zu irreversibler Inhibierung bieten. Allerdings sind mit dieser Methode wegen der Basizität der ϵ‐Aminogruppe in Lysin eine Reihe spezifischer Herausforderungen verbunden. Wir besprechen hier die wichtigen Grundlagen für die Inhibitorplanung, geben historische Beispiele und stellen neue Entwicklungen vor, die das Potenzial von Lysin als Konjugationsstelle in der Wirkstoff‐Forschung belegen.

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Intrinsic reactivity profile of electrophilic moieties to guide covalent drug design: N-α-acetyl-l-lysine as an amine nucleophile

Abstract: Covalent drugs contain a reactive electrophilic moiety or covalent reactive group (CRG), which forms an irreversible bond between the drug and a biological target.

Cited by 50 publications

References 29 publications

Selectively Targeting the Kinome-Conserved Lysine of PI3Kδ as a General Approach to Covalent Kinase Inhibition

Selectively Targeting the Kinome-Conserved Lysine of PI3Kδ as a General Approach to Covalent Kinase Inhibition

Lysine‐Targeting Covalent Inhibitors

Auf Lysin zielende, kovalente Inhibitoren

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