enzymes has become one of the most significant drug targets over the past three
decades. It all started in 1978, when the protein kinase c-SRC was found to share
high similarity to a protein from sarcoma virus and act as an oncogene [1]. In
addition, studies in the early 1980s pointed out that hyperactivation of a protein
kinase (protein kinase C) represents a key mechanism for tumor promotion [2]. The
idea to target this group of enzymes therapeutically was also fueled by findings
showing that naphthalene-sulphonamides were able to block kinases [3]. These
molecules were used as a starting point to further synthetize drugs that inhibit protein
kinases.
One of the key experiments for the development of kinase inhibitors was the
crystallization of protein kinase A in 1991. Susan Taylor and colleagues revealed the
structure of the kinase core for the very first time, giving insight into a key element of
all kinases in the genome. This study demonstrated that residues involved in the
binding of ATP were conserved among kinases [4, 5]. The crystal structure of PKA
gave valuable information for the structural function of these enzymes. However,
since core domains of kinases are highly conserved, the idea of selective inhibition
of a protein kinase was also considered to be a major challenge.
Starting from the late 1980s, molecules targeting more than one kinase with
different efficacies were developed. Some years before that, the only purely isolated
tyrosine protein kinases were epidermal growth factor receptor (EGFR) and insulin
receptor. The new molecules were 1,000-fold more potent against EGFR than against
insulin receptor kinase. Interestingly, these drugs were found to be inactive against
serine/threonine kinases [6]. Based on this evidence, scientists could then develop
more inhibitors against these kinases that show structure/activity relationships.
Later on, new findings strengthened the idea of targeted kinase drug development. In particular, ATP mimics were found to selectively inhibit platelet-derived
growth factor receptor (PDGFR), while they were not potent against other protein
kinases. In addition, a study in the mid-1990s showed that quinoxalines are potent
inhibitors of PDGFR though not able to interact with EGFR. Accordingly,
quinazolines showed the opposite effect [7, 8]. Based on this finding, years later,
Zeneca developed the inhibitor gefitinib that targets EGFR. Since 1988, when the
first study showing targeted inhibition of the catalytic activity of EGFR was
published, the number of protein kinase inhibitor agents developed climbed steadily.
It is interesting to note that although EGFR and receptor tyrosine-protein kinase
erbB-2 (HER2) share high homology, scientists were able to develop selective
molecules against these targets with low cross-reaction already since 1993 [9].
A breakthrough was the first approval of a protein kinase inhibitor by the FDA
(2001). This molecule was imatinib, firstly developed by Zeneca as a PDGFR
inhibitor. Interestingly, it was later shown that the drug had also high efficacy against
BCR-ABL, making it suitable for treatment of chronic myelogenous leukemia
(CML) and acute lymphocytic leukemia (ALL) patients positive for Philadelphia
chromosome [10, 11]. Since 2001, 48 kinase inhibitors have been approved to the
market (Table 1) [12]. The vast majority are drugs against tyrosine protein kinases
and receptors for the treatment of cancer. Only a few, ten of them, target serine/
threonine kinases. The main difficulty of developing selective agents against serine/
threonine kinases is the high similarity of the ATP-binding domain of these
Exploiting Kinase Inhibitors for Cancer Treatment: An Overview of Clinical. . .
127
decades. It all started in 1978, when the protein kinase c-SRC was found to share
high similarity to a protein from sarcoma virus and act as an oncogene [1]. In
addition, studies in the early 1980s pointed out that hyperactivation of a protein
kinase (protein kinase C) represents a key mechanism for tumor promotion [2]. The
idea to target this group of enzymes therapeutically was also fueled by findings
showing that naphthalene-sulphonamides were able to block kinases [3]. These
molecules were used as a starting point to further synthetize drugs that inhibit protein
kinases.
One of the key experiments for the development of kinase inhibitors was the
crystallization of protein kinase A in 1991. Susan Taylor and colleagues revealed the
structure of the kinase core for the very first time, giving insight into a key element of
all kinases in the genome. This study demonstrated that residues involved in the
binding of ATP were conserved among kinases [4, 5]. The crystal structure of PKA
gave valuable information for the structural function of these enzymes. However,
since core domains of kinases are highly conserved, the idea of selective inhibition
of a protein kinase was also considered to be a major challenge.
Starting from the late 1980s, molecules targeting more than one kinase with
different efficacies were developed. Some years before that, the only purely isolated
tyrosine protein kinases were epidermal growth factor receptor (EGFR) and insulin
receptor. The new molecules were 1,000-fold more potent against EGFR than against
insulin receptor kinase. Interestingly, these drugs were found to be inactive against
serine/threonine kinases [6]. Based on this evidence, scientists could then develop
more inhibitors against these kinases that show structure/activity relationships.
Later on, new findings strengthened the idea of targeted kinase drug development. In particular, ATP mimics were found to selectively inhibit platelet-derived
growth factor receptor (PDGFR), while they were not potent against other protein
kinases. In addition, a study in the mid-1990s showed that quinoxalines are potent
inhibitors of PDGFR though not able to interact with EGFR. Accordingly,
quinazolines showed the opposite effect [7, 8]. Based on this finding, years later,
Zeneca developed the inhibitor gefitinib that targets EGFR. Since 1988, when the
first study showing targeted inhibition of the catalytic activity of EGFR was
published, the number of protein kinase inhibitor agents developed climbed steadily.
It is interesting to note that although EGFR and receptor tyrosine-protein kinase
erbB-2 (HER2) share high homology, scientists were able to develop selective
molecules against these targets with low cross-reaction already since 1993 [9].
A breakthrough was the first approval of a protein kinase inhibitor by the FDA
(2001). This molecule was imatinib, firstly developed by Zeneca as a PDGFR
inhibitor. Interestingly, it was later shown that the drug had also high efficacy against
BCR-ABL, making it suitable for treatment of chronic myelogenous leukemia
(CML) and acute lymphocytic leukemia (ALL) patients positive for Philadelphia
chromosome [10, 11]. Since 2001, 48 kinase inhibitors have been approved to the
market (Table 1) [12]. The vast majority are drugs against tyrosine protein kinases
and receptors for the treatment of cancer. Only a few, ten of them, target serine/
threonine kinases. The main difficulty of developing selective agents against serine/
threonine kinases is the high similarity of the ATP-binding domain of these
Exploiting Kinase Inhibitors for Cancer Treatment: An Overview of Clinical. . .
127