protein molecule—to control the activity of its catalytic subunit. Not surprisingly,
kinases are widely studied as druggable targets.
Protein tyrosine kinases (PTKs) are enzymes that phosphorylate specific tyrosine
residues within the sequence of a wide variety of proteins that transmit signals central
to cellular processes. Certain PTKs seem to be involved in tumorigenesis, transforming
normal cells to cells with a neoplastic phenotype. Accordingly, small-molecule
inhibitors of PTKs are being developed as therapeutics. Initial work focused on anili-
noquinazoline congeners. Additional work confirmed that most PTK inhibitors have
common chemical features, including a substituted fused bicyclic ring system combined
with another aromatic ring located off the central bicyclic moiety.
Another important family of kinases for drug discovery is the mitogen-activated pro-
tein kinases (MAPKs). These are proline-directed serine/threonine kinases that activate
their substrates by dual-phosphorylation. MAPK enzymes are activated by a variety of
signals including growth factors and cytokines, discussed in chapter 6. The MAPK
family plays a critical role in cell cycle progression. Small molecule inhibitors of
MAPK may have utility in the treatment of cancer.
Yet another interesting family of kinases is the cyclin-dependent kinases (CDKs).
The cell cycle incorporates the coordinated activities of cellular “checkpoint mole-
cules” to ensure the accurate replication of the genome during cellular division. Since
the CDKs are an integral part of these checkpoint controls, they are compelling targets
for drug design. In early work, flavopiridol (8.42) has been one of the most widely stud-
ied compounds as a CDK inhibitor. Such inhibitors may have a therapeutic role in the
management of cancer.
8.2.7.2 Caspases
Apoptosis is a potentially extremely important target in drug design. Apoptosis and
necrosis are the two fundamental biochemical pathologies that cause cells to die.
Necrosis is death from injury (e.g., burn injury to skin); apoptosis is predestined death
from “old age” and degeneration. Apoptosis and necrosis may be compared as shown
in table 8.1.
Apoptosis is pre-programmed cell death. It is why cells (and eventually humans)
eventually die with age. Apoptosis is the blueprint for death contained within the genetic
code of our cells. Being able to modulate apoptosis would be immensely powerful.
500 MEDICINAL CHEMISTRY