2017
DOI: 10.1021/acs.jcim.7b00553
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Expanding the Armory: Predicting and Tuning Covalent Warhead Reactivity

Abstract: Targeted covalent inhibition is an established approach for increasing the potency and selectivity of potential drug candidates, as well as identifying potent and selective tool compounds for target validation studies. It is evident that identification of reversible recognition elements is essential for selective covalent inhibition, but this must also be achieved with the appropriate level of inherent reactivity of the reactive functionality (or "warhead"). Structural changes that increase or decrease warhead… Show more

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Cited by 147 publications
(199 citation statements)
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“…Other residues have been targeted as well with various warheads, i.e., lysine with activated ester [16] or arylsulfonyl fluoride [20], tyrosine with an arylsulfonyl fluoride [22], or asparagine with an aziridinium ion [17]. Indeed, recent extensions of the diversity in warheads give an opportunity for the fine-tuning of the reactivity [24,25].…”
Section: Introductionmentioning
confidence: 99%
“…Other residues have been targeted as well with various warheads, i.e., lysine with activated ester [16] or arylsulfonyl fluoride [20], tyrosine with an arylsulfonyl fluoride [22], or asparagine with an aziridinium ion [17]. Indeed, recent extensions of the diversity in warheads give an opportunity for the fine-tuning of the reactivity [24,25].…”
Section: Introductionmentioning
confidence: 99%
“…For instance, some covalent bifunctional blockers are designed with deliberately weak reactivity in order to increase stability and to decrease toxicity. In some cases, covalent inhibitors can be designed to be cleared rapidly after blocking the PPI, which could reduce non-mechanismbased toxicity [37,139]. Overcoming toxicity is one of the main bottlenecks preventing covalent inhibitors from entering the market [140].…”
Section: Conclusion Remarks and Perspectivesmentioning
confidence: 99%
“…Additionally, gain of cysteine is a common oncogenic mutation that may provide a handle for personalised cancer therapeutics . The classical electrophilic partner to the thiol is an α,β‐unsaturated system, such as an acrylamide, although a wide range of other electrophiles suitable for targeting such systems have been investigated and extensively reviewed (Figure ) . Cysteine‐targeted covalent chemistry has been indisputably fruitful for delivering safe and relatively selective drugs, and hence is growing into an important weapon in the arsenal of the drug hunter to tackle difficult biological targets …”
Section: Introductionmentioning
confidence: 99%