Table 1). For example, over 80 protein kinases feature a cysteine at the hinge
region’s H2 position (see Fig. 4 and Table 1) while only five kinases with a cysteine
at the neighboring H1 position were identified [7]. Moreover, there is a bias in the
availability of inhibitors targeting individual positions or subsites. While several
locations have remained completely unaddressed so far, 8 out of 11 kinases with a
cysteine at the F2 position (αD À 1) were targeted with covalent inhibitors when this
manuscript was written (February 2019). In the following sections, representative
inhibitors engaging cysteine residues at the respective locations will be highlighted
and the underlying design principles be discussed.
2.2 Approved Covalent Protein Kinase Inhibitors
So far, the bulk of efforts in covalent kinase inhibitor discovery has been directed
toward kinases involved in cancer [39, 40]. The tremendous interest in covalent
kinase targeting is highlighted by over 60 patents disclosed only between 2010 and
2013 [41]. Currently, six covalent kinase inhibitors are approved by the FDA
(Fig. 5): afatinib (BIBW-2992, 1), dacomitinib (PF-00299804, 2), neratinib
(HKI-272, 3), osimertinib (AZD9291, 4), ibrutinib (PCI-32765, 5), and acalabrutinib
(ACP-196, 6). Among these, the first one to gain FDA approval (07/2013) was
afatinib, a gefitinib (7)-derived second-generation EGFR/ErbB(HER) family kinase
inhibitor (vide supra) developed by Boehringer Ingelheim, which is used in the
therapy of metastatic non-small-cell lung cancer (NSCLC) driven by activating
EGFR-mutations [42]. This compound hits a cysteine in the F2 position of the
EGFR kinase domain (Cys797), which is also present in ErbB2 and ErbB4 but not
in the pseudokinase ErbB3. Later in 2013, ibrutinib, an inhibitor addressing an
equivalently positioned cysteine in Bruton’s tyrosine kinase (BTK), was approved
for the treatment of mantle cell lymphoma. The marketing authorization was later
expanded to other conditions including chronic lymphocytic leukemia (2014) and
chronic graft versus host disease (2017) [43] making ibrutinib one of the few small
molecule kinase inhibitors therapeutically used for the modulation of immune
response in a non-oncology setting. Osimertinib, a third-generation mutant-selective
EGFR inhibitor, was approved in 2015 for metastatic NSCLC haboring the EGFRT790M resistance mutation [44]. In July 2017, the FDA granted approval to
neratinib, a quinoline-derived pan-ErbB-inhibitor for adjuvant treatment of early
stage HER2-positive breast cancer. In October 2017, acalabrutinib, an ibrutinibderived second-generation BTK inhibitor featuring a but-2-yne amide warhead,
gained marketing authorization for the treatment of mantle cell lymphoma
[45]. The sixth and most recently approved covalent kinase inhibitor is dacomitinib,
a close structural analog of afatinib developed by Pfizer and employed in the
treatment of metastatic NSCLC with activating EGFR mutations (L858R) or exon
19 deletions [46].
52
M. Gehringer
region’s H2 position (see Fig. 4 and Table 1) while only five kinases with a cysteine
at the neighboring H1 position were identified [7]. Moreover, there is a bias in the
availability of inhibitors targeting individual positions or subsites. While several
locations have remained completely unaddressed so far, 8 out of 11 kinases with a
cysteine at the F2 position (αD À 1) were targeted with covalent inhibitors when this
manuscript was written (February 2019). In the following sections, representative
inhibitors engaging cysteine residues at the respective locations will be highlighted
and the underlying design principles be discussed.
2.2 Approved Covalent Protein Kinase Inhibitors
So far, the bulk of efforts in covalent kinase inhibitor discovery has been directed
toward kinases involved in cancer [39, 40]. The tremendous interest in covalent
kinase targeting is highlighted by over 60 patents disclosed only between 2010 and
2013 [41]. Currently, six covalent kinase inhibitors are approved by the FDA
(Fig. 5): afatinib (BIBW-2992, 1), dacomitinib (PF-00299804, 2), neratinib
(HKI-272, 3), osimertinib (AZD9291, 4), ibrutinib (PCI-32765, 5), and acalabrutinib
(ACP-196, 6). Among these, the first one to gain FDA approval (07/2013) was
afatinib, a gefitinib (7)-derived second-generation EGFR/ErbB(HER) family kinase
inhibitor (vide supra) developed by Boehringer Ingelheim, which is used in the
therapy of metastatic non-small-cell lung cancer (NSCLC) driven by activating
EGFR-mutations [42]. This compound hits a cysteine in the F2 position of the
EGFR kinase domain (Cys797), which is also present in ErbB2 and ErbB4 but not
in the pseudokinase ErbB3. Later in 2013, ibrutinib, an inhibitor addressing an
equivalently positioned cysteine in Bruton’s tyrosine kinase (BTK), was approved
for the treatment of mantle cell lymphoma. The marketing authorization was later
expanded to other conditions including chronic lymphocytic leukemia (2014) and
chronic graft versus host disease (2017) [43] making ibrutinib one of the few small
molecule kinase inhibitors therapeutically used for the modulation of immune
response in a non-oncology setting. Osimertinib, a third-generation mutant-selective
EGFR inhibitor, was approved in 2015 for metastatic NSCLC haboring the EGFRT790M resistance mutation [44]. In July 2017, the FDA granted approval to
neratinib, a quinoline-derived pan-ErbB-inhibitor for adjuvant treatment of early
stage HER2-positive breast cancer. In October 2017, acalabrutinib, an ibrutinibderived second-generation BTK inhibitor featuring a but-2-yne amide warhead,
gained marketing authorization for the treatment of mantle cell lymphoma
[45]. The sixth and most recently approved covalent kinase inhibitor is dacomitinib,
a close structural analog of afatinib developed by Pfizer and employed in the
treatment of metastatic NSCLC with activating EGFR mutations (L858R) or exon
19 deletions [46].
52
M. Gehringer