Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles

Iana M Serafimova; Miles A Pufall; Shyam Krishnan; Katarzyna Duda; Michael S Cohen; Rebecca L Maglathlin; Jesse M McFarland; Rand M Miller; Morten Frödin; Jack Taunton

doi:10.1038/nchembio.925

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Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles

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Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles

Iana M Serafimova, Miles A Pufall, Shyam Krishnan, Katarzyna Duda, Michael S Cohen, Rebecca L Maglathlin, Jesse M McFarland, Rand M Miller, Morten Frödin and Jack Taunton

Nature chemical biology, Vol.8(5), pp.471-476

2012

DOI: 10.1038/nchembio.925

PMCID: PMC3657615

PMID: 22466421

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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, yet 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, RSK. 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.

Details

Title: Subtitle: Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles
Creators: Iana M Serafimova - Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, California 94158, USA
Miles A Pufall - Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158, USA
Shyam Krishnan - Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158, USA
Katarzyna Duda - Biotech Research & Innovation Centre and Centre for Epigenetics, University of Copenhagen, Denmark
Michael S Cohen - Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, California 94158, USA
Rebecca L Maglathlin - Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, California 94158, USA
Jesse M McFarland - Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158, USA
Rand M Miller - Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, California 94158, USA
Morten Frödin - Biotech Research & Innovation Centre and Centre for Epigenetics, University of Copenhagen, Denmark
Jack Taunton - Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, California 94158, USA
Resource Type: Journal article
Publication Details: Nature chemical biology, Vol.8(5), pp.471-476
DOI: 10.1038/nchembio.925
PMID: 22466421
PMCID: PMC3657615
NLM abbreviation: Nat Chem Biol
ISSN: 1552-4450
eISSN: 1552-4469
Language: English
Date published: 2012
Academic Unit: Biochemistry and Molecular Biology
Record Identifier: 9984024510202771

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