title: Design of reversible, cysteine-targeted Michael acceptors guided by kinetic and computational analysis.
abstract: 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.
authors.affiliation: Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California-San Francisco , San Francisco, California 94158, United States.
authors.forename: Shyam
authors.initials: S
authors.lastname: Krishnan
authors.forename: Rand M
authors.initials: RM
authors.lastname: Miller
authors.forename: Boxue
authors.initials: B
authors.lastname: Tian
authors.forename: R Dyche
authors.initials: RD
authors.lastname: Mullins
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Jacobson
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
mesh_terms: D000181:Acrylonitrile / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003545:Cysteine / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D011522:Protons; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011522:Protons; D011494:Protein Kinases; D003545:Cysteine; D000181:Acrylonitrile