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Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles.

<div class='caption-title'>Thiol reactivity of electron-deficient olefins</div>
<div class='caption-title'>Sustained, reversible inhibition of RSK2-CTD by doubly activated Michael acceptors</div>
<div class='caption-title'>Sustained inhibition of cellular RSK1/2 by CN-NHiPr</div>
Serafimova IM, Pufall MA, Krishnan S, Duda K, Cohen MS, Maglathlin RL, McFarland JM, Miller RM, Frödin M, Taunton J
OpenAccess logo Nat Chem Biol 8 471-6 (2012)
Cited: 215 times
EuropePMC logo PMID: 22466421

Abstract

Targeting noncatalytic cysteine residues with irreversible acrylamide-based inhibitors is a powerful approach for enhancing pharmacological potency and selectivity. Nevertheless, concerns about off-target modification motivate the development of reversible cysteine-targeting strategies. Here we show that electron-deficient olefins, including acrylamides, can be tuned to react with cysteine thiols in a rapidly reversible manner. Installation of a nitrile group increased the olefins' intrinsic reactivity, but, paradoxically, eliminated the formation of irreversible adducts. Incorporation of these electrophiles into a noncovalent kinase-recognition scaffold produced slowly dissociating, covalent inhibitors of the p90 ribosomal protein S6 kinase RSK2. A cocrystal structure revealed specific noncovalent interactions that stabilize the complex by positioning the electrophilic carbon near the targeted cysteine. Disruption of these interactions by protein unfolding or proteolysis promoted instantaneous cleavage of the covalent bond. Our results establish a chemistry-based framework for engineering sustained covalent inhibition without accumulating permanently modified proteins and peptides.

Reviews - 4d9u mentioned but not cited (5)

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