Page 1228 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPTER 88 Protein Kinase Antagonists 1191

proteins, all of which share structural similarities with PTKs. which binds directly to a methyl group of the phenyl ring of the
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Third, despite the many potential ways of designing a small- Abl kinase inhibitor imatinib. Across the collective kinase
molecule kinase inhibitor, in practice, the majority work by sitting superfamily, almost any amino acid can appear as the gatekeeper,
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within the ATP-binding pocket. A priori then, one might conclude although in practice, it is typically a bulky nonpolar residue
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that it would be impossible to generate an antagonist that did (methionine, tyrosine, phenylalanine, lysine). In principle, as
not target some other essential ATP-dependent process. Fortu- more detailed structural information emerges from the many
nately though, this skeptical view does not reflect reality. protein kinases, capitalizing on subtle differences in structure is
expected to lead to the discovery of novel agents with improved
THERAPEUTIC PRINCIPLES potency and specificity. For instance, cyclin-dependent kinase 2
(CDK2) contains an additional pocket on its C-lobe next to the
Protein Kinase Inhibitors As Drugs ATP-binding pocket. Several CDK2-specific inhibitors exploit
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this by binding to both pockets.
• Drugs can inhibit protein kinases with a high degree of specificity.
• Multi-kinase inhibitors can be well tolerated and be more efficacious Of further structural significance is the emergence of tumor
than single kinase inhibitors (e.g., second-generation Abl kinase drug resistance in response to the chronic use of protein kinase
inhibitors). inhibitors. Mutant forms of BCR-Abl, Kit, and epidermal growth
• Conversely, unacceptable toxicity has limited the creation of clinical factor receptor (EGFR) have been associated with loss of drug
inhibitors to particular kinase members (e.g., p38 MAPK inhibitors). activity and disease relapse. Interestingly, one of the most common
sites of mutation is the otherwise conserved “gatekeeper residue.”
The appearance of such mutations that cause resistance to imatinib
Imatinib and Other First-Generation Protein Tyrosine have led to the need for other drugs with broader activity against
Kinases Inhibitors a number of kinases. Thus in the setting of oncology, “multikinase”
The first protein kinase inhibitor approved by the US Food and inhibitors, including dasatinib and sunitinib, have now entered
Drug Administration (FDA) is imatinib (see Table 88.3). The clinical practice and have been approved by the FDA. Although
mutated form of the Abl tyrosine kinase BCR-Abl represents a a major problem in the treatment of malignancy, this is less
fusion protein that is the result of a chromosomal translocation likely to be an issue in the treatment of autoimmune disease;
(Philadelphia chromosome) observed in patients suffering from nonetheless, drugs used for oncological indications often end
chronic myeloid leukemia (CML). The pathognomonic presence up being quite useful in the treatment of autoimmunity. Such
of BCR-Abl in CML has led to it becoming one of the most precedents include cyclophosphamide, azathioprine, and metho-
intensively studied PTKs. The fusion protein consists of an trexate. Therefore it is not unreasonable to speculate that a number
oligomerization domain, a PH domain, and a Dbl/cdc24 guanine of the kinase inhibitors developed as anticancer agents may
nucleotide exchange factor homology domain that contains the ultimately be used to treat inflammatory or immunological
N-terminal breakpoint cluster region (BCR) of the protein. The diseases.
Abl half of the fusion protein contains a tyrosine kinase domain, An unexpected finding for a clinically well-tolerated inhibitor,
a Src homology 2 (SH2) domain, and a DNA-binding domain, which was originally thought to be a highly specific inhibitor
together with nuclear localization and nuclear export motifs. for Abl kinase, was the realization that imatinib has activity
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The Abl kinase is constitutively active within the fusion protein against several other PTKs. Consequently, it has been found to
and has been implicated in initiating numerous signaling pathways be useful in the treatment of a number of cancers that do not
that mediate cell survival and proliferation. In view of this, and have abnormal Abl kinase activity. Imatinib has been used to
the essential requirement for BCR-Abl kinase activity in CML, treat gastrointestinal (GI) stromal tumor and hypereosinophilic
it was thought to be an ideal target despite the aforementioned syndrome through its effects on Kit and PDGFR-FIPIL1 kinases,
caveats with targeting protein kinases. As predicted, imatinib respectively. In spite of efforts to develop highly specific kinase
has revolutionized the treatment of CML. This inhibitor has inhibitors, there is increasing evidence that a partial inhibition
been remarkably successful in arresting the progression of the of multiple kinases is potentially less toxic than originally feared
CML but is also well tolerated with acceptable side effects. 3 and may be important for the efficacy of many inhibitors.
Although conservation of the kinase ATP-binding pocket has Second-generation Abl inhibitors, including dasatinib and
posed a potential problem for designing kinase inhibitors, in bosutinib, are less selective than imatinib. This lack of specificity
practice, this has not happened for several reasons. Although may contribute to their improved response rates in the treatment
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different kinases may be structurally similar in an active ATP- of CML. With respect to immune-mediated diseases, imatinib
bound conformation, the inactive conformation is substantially is used in the clinic for the treatment of fibrotic diseases, including
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less frequent and can be used to generate selective inhibitors. skin fibrosis associated with chronic graft-versus-host disease
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The ATP-binding region is made up of six polar amino acid (GvHD). At the time of writing, there are >20FDA-approved
residues that are invariant across whole families of kinases; small molecule kinase inhibitors, most which are approved for
similarly, there are numerous lipophilic residues that are highly oncological indications. In addition, there are numerous other
conserved. In addition, this critical region contains an amino kinase inhibitors in clinical trial or development (summarized
acid whose amide carbonyl binds to N-6 of adenine in the active in Table 88.3). Besides small-molecule direct inhibitors of kinases,
conformation. The side chain of this amino acid sticks into the which typically block the ATP-binding pocket, there are several
reaction pocket in the inactive state and, for this reason, is referred alternative strategies. These include small inhibiting RNA to
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to as “the gatekeeper residue.” As the side chain is not involved block protein expression of the kinase Syk (Excellair; ZaBeCor
in direct ATP binding, it varies across kinases, and variation of Pharmaceutical Co., Bala Cynwyd, PA), inhibition of associated
this gatekeeper residue is exploited by a number of inhibitors proteins required to activate the target kinase as in the rapamycin
that are able to bind the inactive conformation of specific kinases. derivatives and the use of monoclonal antibodies (mAbs) that
In the case of Abl kinase, the gatekeeper residue is threonine, inhibit ligand-dependent activation of transmembrane receptor