Document Report Card
Basic Information
ID: ALA5137094
Journal: J Med Chem
Title: Construction of Covalent Bisubstrate Inhibitor of Protein Kinase Reacting with Cysteine Residue at Substrate-Binding Site.
Authors: Sõrmus T, Lavogina D, Teearu A, Enkvist E, Uri A, Viht K.
Abstract: Recent clinical success with targeted covalent inhibitors points to new possibilities for development of protein kinase (PK)-targeted drugs by exploiting reactive cysteine residues in and around the ATP-binding site. However, more than 300 human PKs lack cysteine residues in the ATP-binding site. Here, we report the first covalent bisubstrate PK inhibitor whose electrophilic warhead reaches outside the ATP-binding site and reacts with a distant cysteine residue. A series of covalent inhibitors and their reversible counterparts were synthesized and characterized. The most potent reversible inhibitor possessed picomolar affinity and its cysteine-reactive counterpart revealed high value of kinact/KI ratio (6.2 × 107 M-1 s-1) for the reaction with the catalytic subunit of cAMP-dependent PK (PKAc). Under optimized conditions, fluorescent dye-labeled covalent inhibitors demonstrated PKA-selectivity in the cell lysate and reacted with several proteins inside live cells, including PKAc. The disclosed compounds serve as leads for targeting PKs possessing an analogously positioned cysteine residue.
CiteXplore: 35960538