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New Cysteine Covalent Modification Strategies Enable Advancement of Proteome‐wide Selectivity of Kinase Modulators
Author(s) -
Guan Ivy,
Williams Kayla,
Pan Jolyn,
Liu Xuyu
Publication year - 2021
Publication title -
asian journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.846
H-Index - 44
eISSN - 2193-5815
pISSN - 2193-5807
DOI - 10.1002/ajoc.202100036
Subject(s) - covalent bond , chemistry , selectivity , electrophile , cysteine , nucleophile , combinatorial chemistry , kinase , reactivity (psychology) , rational design , sortase , biochemistry , enzyme , nanotechnology , organic chemistry , gene , materials science , catalysis , medicine , alternative medicine , pathology , bacterial protein
There has been tremendous progress in covalent inhibitors as evidenced by the ascent of innovative electrophilic warheads with suppressed non‐specific reactivity but enhanced capacity for proximity‐driven covalent reactions with nucleophilic residues in the targeted site. Kinases, a central player in cancers, autoimmune disorders and chronic diseases, represent a highly targeted class of enzymes by covalent inhibitors. However, innovative strategies to afford high selectivity in target recognition remain a pressing need. This minireview focuses on four promising strategies to achieve superior target selectivity through rational design of the covalent engagement. Special emphasis is placed on examples where the selectivity had arisen by complementing the reactivity of protein cysteines with electrophilic warheads specified for distinct covalent chemistry, or inspired from native electrophile signalling in cells.