Top Med Chem (2021) 36: 43–94
https://doi.org/10.1007/7355_2020_103
© Springer Nature Switzerland AG 2020
Published online: 23 June 2020
Covalent Kinase Inhibitors: An Overview
Matthias Gehringer
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
2 Covalent Protein Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
2.1 The Protein Kinases’ Cysteinome . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 50
2.2 Approved Covalent Protein Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
2.3 Natural Products as Covalent Protein Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
2.4 Development of Inhibitors Targeting Cysteines in the Front Region . . . . . . . . . . . . . . . . . 57
2.5 Development of Inhibitors Targeting Cysteines around the P-Loop and in the Roof
Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
2.6 Development of Inhibitors Targeting Cysteines in the Hinge Region . . . . . . . . . . . . . . . . 72
2.7 Development of Inhibitors Targeting Cysteines Around the DFG Motif
and in the Activation Segment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
2.8 Development of Inhibitors Targeting Remote Cysteines or Inactive Conformations . . . 76
2.9 Development of Inhibitors Targeting Cysteines in Allosteric Pockets . . . . . . . . . . . . . . . . 78
2.10 Development of Inhibitors Targeting Lysine or Tyrosine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
3 Summary and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Abstract Covalent targeting has experienced a revival in the last decade, especially
in the area of protein kinase inhibitor development. Generally, covalent inhibitors
make use of an electrophilic moiety often termed “warhead” to react with a nucleophilic amino acid, most frequently a cysteine. High efficacy and excellent selectivity in the kinome have been achieved by addressing poorly conserved, non-catalytic
cysteine residues with so-called targeted covalent inhibitors (TCIs). Despite the
challenges associated with covalent modifiers, application of the TCI approach for
the discovery of new treatments has been very successful with six covalent kinase
inhibitors having gained approval in the last few years. A multitude of reactive
chemical probes and tool compounds has further been developed. Beside cysteine,
other nucleophilic amino acids including tyrosine and lysine have also been
M. Gehringer (*)
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences,
Eberhard Karls University of Tübingen, Tübingen, Germany
e-mail: matthias.gehringer@uni-tuebingen.de
https://doi.org/10.1007/7355_2020_103
© Springer Nature Switzerland AG 2020
Published online: 23 June 2020
Covalent Kinase Inhibitors: An Overview
Matthias Gehringer
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
2 Covalent Protein Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
2.1 The Protein Kinases’ Cysteinome . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 50
2.2 Approved Covalent Protein Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
2.3 Natural Products as Covalent Protein Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
2.4 Development of Inhibitors Targeting Cysteines in the Front Region . . . . . . . . . . . . . . . . . 57
2.5 Development of Inhibitors Targeting Cysteines around the P-Loop and in the Roof
Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
2.6 Development of Inhibitors Targeting Cysteines in the Hinge Region . . . . . . . . . . . . . . . . 72
2.7 Development of Inhibitors Targeting Cysteines Around the DFG Motif
and in the Activation Segment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
2.8 Development of Inhibitors Targeting Remote Cysteines or Inactive Conformations . . . 76
2.9 Development of Inhibitors Targeting Cysteines in Allosteric Pockets . . . . . . . . . . . . . . . . 78
2.10 Development of Inhibitors Targeting Lysine or Tyrosine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
3 Summary and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Abstract Covalent targeting has experienced a revival in the last decade, especially
in the area of protein kinase inhibitor development. Generally, covalent inhibitors
make use of an electrophilic moiety often termed “warhead” to react with a nucleophilic amino acid, most frequently a cysteine. High efficacy and excellent selectivity in the kinome have been achieved by addressing poorly conserved, non-catalytic
cysteine residues with so-called targeted covalent inhibitors (TCIs). Despite the
challenges associated with covalent modifiers, application of the TCI approach for
the discovery of new treatments has been very successful with six covalent kinase
inhibitors having gained approval in the last few years. A multitude of reactive
chemical probes and tool compounds has further been developed. Beside cysteine,
other nucleophilic amino acids including tyrosine and lysine have also been
M. Gehringer (*)
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences,
Eberhard Karls University of Tübingen, Tübingen, Germany
e-mail: matthias.gehringer@uni-tuebingen.de