Developing irreversible inhibitors of the protein kinase cysteinome

By Qingsong Liu, Yogesh Sabnis, Zheng Zhao, Tinghu Zhang, S. Buhrlage, L. Jones, Nathanael S. Gray. Chemistry and Biology, 2013

612 citations recorded by the source corpus.

Protein kinases are a large family of approximately 530 highly conserved enzymes that transfer a γ-phosphate group from ATP to a variety of amino acid residues such as tyrosine, serine and threonine which serves as a ubiquitous mechanism for cellular signal transduction. The clinical success of a number of kinase-directed drugs and the frequent observation of disease causing mutations in protein kinases suggest that a large number of kinases may represent therapeutically relevant targets. To-date the majority of clinical and preclinical kinase inhibitors are ATP-competitive, non-covalent inhibitors that achieve selectivity through recognition of unique features of particular protein kinases. Recently there has been renewed interest in the development of irreversible inhibitors that form covalent bonds with cysteine or other nucleophilic residues in the ATP-binding pocket. Irreversible kinase inhibitors have a number of potential advantages including prolonged pharmacodynamics, suitability for rational design, high potency and ability to validate pharmacological specificity through mutation of the reactive cysteine residue. Here we review recent efforts to develop cysteine-targeted irreversible protein kinase inhibitors and discuss their modes of recognizing the ATP-binding pocket and their biological activity profiles. In addition, we provided an informatics assessment of the potential ‘kinase-cysteinome’ and discuss strategies for the efficient development of new covalent inhibitors.

Subfields: Infectious Diseases, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/b3acb80f8893dd742262011a5ee986836481a5b7

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Citations in the corpus

Targeting the PI5P4K lipid kinase family in cancer using covalent inhibitors (2020, background): “Covalent irreversible inhibitors characteristically exhibit an enhanced potency and prolonged pharmacodynamics due to permanent disabling of kinase enzymatic activity, and high selectivity as covalent inhibitors will only bind irreversibly to a kinase with an appropriately placed cysteine, within th”
CavityPlus: a web server for protein cavity detection with pharmacophore modelling, allosteric site identification and covalent ligand binding ability prediction (2018, background): “These two Cys sites may attract a renewed interest in developing cysteine-targeted irreversible protein kinase inhibitors (29).”
Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. (2018, background): “There are 200 kinases with reactive cysteines near the ATP pocket (Liu et al., 2013), and likewise extends to non-kinase proteins with reactive cysteines (Strelow, 2017) that if targeted could produce an unwanted idiosyncratic toxicity.”
Kinase-targeted cancer therapies: progress, challenges and future directions (2018, background): “Other advantages include prolonged pharmacodynamics, suitability for rational design, high potency, and ability to validate pharmacological specificity through mutation of the reactive cysteine residue [119].”