Design of Reversible, Cysteine-Targeted Michael Acceptors Guided by Kinetic and Computational Analysis

Electrophilic probes that covalently modify a cysteine thiol often show enhanced pharmacological potency and selectivity. Although reversible Michael acceptors have been reported, the structural requirements for reversibility are poorly understood. Here, we report a novel class of acrylonitrile-base...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2014-09, Vol.136 (36), p.12624-12630
Main Authors: Krishnan, Shyam, Miller, Rand M, Tian, Boxue, Mullins, R. Dyche, Jacobson, Matthew P, Taunton, Jack
Format: Article
Language:English
Subjects:
Acrylonitrile - chemical synthesis
Acrylonitrile - chemistry
Acrylonitrile - pharmacology
Acrylonitriles
Affinity
Cell Line, Tumor
Computation
Covalence
Cysteine - chemistry
Design engineering
Dose-Response Relationship, Drug
Humans
Inhibitors
Kinases
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Protein Kinases - metabolism
Protons
Structure-Activity Relationship
Thiols
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Summary:Electrophilic probes that covalently modify a cysteine thiol often show enhanced pharmacological potency and selectivity. Although reversible Michael acceptors have been reported, the structural requirements for reversibility are poorly understood. Here, we report a novel class of acrylonitrile-based Michael acceptors, activated by aryl or heteroaryl electron-withdrawing groups. We demonstrate that thiol adducts of these acrylonitriles undergo β-elimination at rates that span more than 3 orders of magnitude. These rates correlate inversely with the computed proton affinity of the corresponding carbanions, enabling the intrinsic reversibility of the thiol-Michael reaction to be tuned in a predictable manner. We apply these principles to the design of new reversible covalent kinase inhibitors with improved properties. A cocrystal structure of one such inhibitor reveals specific noncovalent interactions between the 1,2,4-triazole activating group and the kinase. Our experimental and computational study enables the design of new Michael acceptors, expanding the palette of reversible, cysteine-targeted electrophiles.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja505194w