addressed with suitable electrophiles and covalent-reversible chemistry has recently
complemented our toolbox for designing covalent kinase inhibitors. Covalent
ligands have also been used in the framework of chemical-genetics approaches or
to tackle allosteric pockets, which are often difficult to address.
This chapter aims at providing a general introduction to covalent kinase inhibitors
and an overview of the current state of research highlighting major targeting
strategies, developments, and advances in this field. More detailed information on
certain targets and approaches can be found in dedicated chapters of this book.
Keywords Chemical probes, Electrophilic warheads, Kinase inhibitors, Structurebased drug design, Targeted covalent inhibitors
1 Introduction
Covalent inhibitors have a long history in medicinal chemistry and various covalent
modifiers, such as aspirin, β-lactam antibiotics or omeprazole, to name just a few,
have been among the most frequently used drugs for decades [1]. However, many of
the drug classes acting via a covalent mechanism have been discovered serendipitously. Due to concerns about their potential for haptenization and idiosyncratic
toxicity as well as side effects or toxicity arising from irreversible off-target labeling,
reactive compounds have long been regarded with skepticism by pharmaceutical
companies [2, 3]. Since the beginning of the twenty-first century, however, we have
seen a resurgence of covalent targeting strategies in medicinal chemistry. Targeted
covalent inhibitors (TCIs) which have been defined as “inhibitors bearing a bondforming functional group of low reactivity that, following binding to the target
protein, is positioned to react rapidly with a specific non-catalytic residue at the
target site” [1] are now becoming more and more common especially in the field of
protein kinase drug discovery [4–7].
The renewed interest in covalent inhibitors is based on the growing awareness
that a well-designed TCI can offer a variety of benefits over classical, non-covalently
binding molecules (an excellent review summarizing the opportunities and pitfalls
associated with the development of covalent-modifier drugs has recently been
provided by De Cesco et al. [8]). Currently, most TCIs address non-catalytic cysteine
residues with an electrophilic headgroup termed “warhead” [9], which is highlighted
in red throughout this chapter. Thereby, TCIs can make use of the combined
specificity of two orthogonal selectivity filters: (1) reversible recognition and
(2) the covalent bond-forming reaction. Consequently (and counterintuitively),
covalent targeting can increase selectivity provided that the intrinsic reactivity of
the warhead is low enough to hit only residues juxtaposed by the reversible binding
event [3, 7]. This second selectivity filter is particularly useful when targeting the
protein kinases’ ATP pocket, which features a high overall similarity throughout the
44
M. Gehringer
complemented our toolbox for designing covalent kinase inhibitors. Covalent
ligands have also been used in the framework of chemical-genetics approaches or
to tackle allosteric pockets, which are often difficult to address.
This chapter aims at providing a general introduction to covalent kinase inhibitors
and an overview of the current state of research highlighting major targeting
strategies, developments, and advances in this field. More detailed information on
certain targets and approaches can be found in dedicated chapters of this book.
Keywords Chemical probes, Electrophilic warheads, Kinase inhibitors, Structurebased drug design, Targeted covalent inhibitors
1 Introduction
Covalent inhibitors have a long history in medicinal chemistry and various covalent
modifiers, such as aspirin, β-lactam antibiotics or omeprazole, to name just a few,
have been among the most frequently used drugs for decades [1]. However, many of
the drug classes acting via a covalent mechanism have been discovered serendipitously. Due to concerns about their potential for haptenization and idiosyncratic
toxicity as well as side effects or toxicity arising from irreversible off-target labeling,
reactive compounds have long been regarded with skepticism by pharmaceutical
companies [2, 3]. Since the beginning of the twenty-first century, however, we have
seen a resurgence of covalent targeting strategies in medicinal chemistry. Targeted
covalent inhibitors (TCIs) which have been defined as “inhibitors bearing a bondforming functional group of low reactivity that, following binding to the target
protein, is positioned to react rapidly with a specific non-catalytic residue at the
target site” [1] are now becoming more and more common especially in the field of
protein kinase drug discovery [4–7].
The renewed interest in covalent inhibitors is based on the growing awareness
that a well-designed TCI can offer a variety of benefits over classical, non-covalently
binding molecules (an excellent review summarizing the opportunities and pitfalls
associated with the development of covalent-modifier drugs has recently been
provided by De Cesco et al. [8]). Currently, most TCIs address non-catalytic cysteine
residues with an electrophilic headgroup termed “warhead” [9], which is highlighted
in red throughout this chapter. Thereby, TCIs can make use of the combined
specificity of two orthogonal selectivity filters: (1) reversible recognition and
(2) the covalent bond-forming reaction. Consequently (and counterintuitively),
covalent targeting can increase selectivity provided that the intrinsic reactivity of
the warhead is low enough to hit only residues juxtaposed by the reversible binding
event [3, 7]. This second selectivity filter is particularly useful when targeting the
protein kinases’ ATP pocket, which features a high overall similarity throughout the
44
M. Gehringer