Anticancer Agents - Drug Design and Discovery - page 390

seen in Figure 23.7B) found in a screen for protein kinase C (PKC) inhibitors. This compound
showed good lead-like properties and could be further optimized with straightforward chemistry to
improve activity, selectivity as well as drug like properties. Thus, the addition of a 3¢-pyridyl group
at the 3¢-position of the pyrimidine gave compounds with superior activity as PKC inhibitors in cel-
lular assays. It was further found that derivatives with an amide group in the phenyl ring provided
inhibitory activity against tyrosine kinases, such as the BCR-ALB kinase (Figure 23.7B, compound
A). Subsequent SAR studies suggested that a substitution at position 6 of the diaminophenyl ring
abolished PKC inhibitory activity while retaining activity for BCR-ABL kinase, which was con-
i rmed by the introduction of a methyl group in this position (Figure 23.7B, compound B). Further
modii cation was, however, needed due to the low solubility and bioavailability found for these
compounds. Introduction of a highly polar side chain (an N -methylpiperazine) gave a marked
improvement of both solubility and oral bioavailability. To avoid the mutagenic potential of ani-
line moieties, a spacer was introduced between the phenyl ring and the nitrogen atom that now
afforded the best compound in the series, Gleevec (Figure 23.7B, compound C). Computational
chemistry docking and x-ray crystallography shows that Gleevec binds at the ATP-binding site
of an inactive form of the kinase. The high specii city of Gleevec is explained by this unusual
binding as well as some strong interactions of the N -methylpiperazine group with the ABL kinase
backbone (Figure 23.7C).
23.2.6 H ERCEPTIN
In the previous sections, we have looked at small molecule inhibitors of various cancer pathways
and targets. A totally different approach is to use natures' own building blocks and principles to
target cancer calls selectively for destruction (see also Chapter 22). One of the best examples is the
humanized antibody Trastuzumab or Herceptin developed by Genentec targeting the HER2/Neu
receptor that is often over expressed in breast cancers. The development of antibody-based antican-
cer therapies goes back to the 1950s and the i rst experiments used polyclonal antisera, but their use
was hampered by the inherent problems with the polyclonal origin of the antibodies. This problem
was alleviated by the 1970s when the application of hybridoma cell culture allowed for the prepara-
tion of monoclonal antibodies. At the beginning of clinical experiments using such antibodies, fully
murine, rabbit, or rat antibodies were investigated but their applications were often associated with
severe clinical problems as a result of anaphylaxis due to the patient's immune response toward
these forcing molecules. Today these problems have been effectively solved by the use of so-called
humanized antibodies in which the invariable regions have been replaced with the homologous
human sequences. The antibodies can also be “armed” with radioisotopes or cellular toxins that are
then effectively targeted to the surface of their target cells, or even aimed with activators of prod-
rugs, leading to high concentrations of the active substances in targeted cells.
The HER2 receptor also called Neu or ErbB2 is a member of the epidermal growth factor recep-
tor (EGFR) family of transmembrane tyrosine kinases. It is composed of an extracellular domain,
a hydrophilic transmembrane domain, and an intracellular domain harboring its tyrosine kinase
activity which when activated provides the upstream signal for activating cellular signaling path-
ways responsible for cell proliferation such as the Ras-MAPK and PI3K pathways (Figure 23.1).
In contrast to the other EGFR receptor members, HER2 has no identii ed binding ligand, but its
tyrosine kinase activity can be activated upon dimerization of two HER2 receptors and also upon
heterodimerization of HER2 with other EGFR family members. HER2 is often overexpressed in
breast cancers, which can be caused by gene duplication as well as transcriptional upregulation.
This in turn leads to hyper activation of its downstream pathways mentioned above, accelerating,
and sustaining tumor growth (Figure 23.1). Therefore, there is a clear rational for targeting the
HER2/Neu receptor in breast cancers in cases where it is overexpressed (20%-30% of metastatic
breast cancers). Large clinical trails were necessary to establish that the HER2/Neu receptor has
to be overexpressed to high levels in order for Herceptin to provide a therapeutic benei t. This