New Cysteine Covalent Modification Strategies Enable Advancement of Proteome‐wide Selectivity of Kinase Modulators

Ivy Guan, Kayla Williams, Jolyn Pan, Xuyu Liu

doi:10.1002/ajoc.202100036

New Cysteine Covalent Modification Strategies Enable Advancement of Proteome‐wide Selectivity of Kinase Modulators

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Ivy Guan

School of Chemistry The Heart Research Institute The University of Sydney Sydney New South Wales 2006 Australia
Kayla Williams

School of Chemistry The University of Sydney Sydney New South Wales 2006 Australia
Jolyn Pan

Faculty of Science & Engineering The University of Waikato 124 Hillcrest Road, Hillcrest Hamilton 3216 New Zealand
Xuyu Liu

School of Chemistry The Heart Research Institute The University of Sydney Sydney New South Wales 2006 Australia

説明

<jats:title>Abstract</jats:title><jats:p>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.</jats:p>