4mao

Publication Abstract from PubMed

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 beta-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.

Design of reversible, cysteine-targeted Michael acceptors guided by kinetic and computational analysis.,Krishnan S, Miller RM, Tian B, Mullins RD, Jacobson MP, Taunton J J Am Chem Soc. 2014 Sep 10;136(36):12624-30. doi: 10.1021/ja505194w. Epub 2014, Sep 2. PMID:25153195^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.