Anti-hormone Therapy

192 C. Garcia-Echeverria
Currently, three rapamycin derivatives—CCI-779 (compound 32, Fig.6),
RAD-001 (compound 33, Fig. 6), and AP-23573 (compound 34, Fig.6)—are
being evaluated in cancer clinical trials. All these mTOR inhibitors have
shown potent cytostatic activity in cellular settings and in vivo antitumor
activity in a variety of hematological and solid tumor preclinical models as
single agents and in combination with standard cancer therapeutics, targeted
anticancer agents, and radiation [2, 151, 156]. It is important to mention that
CCI-779 and RAD-001 are pro-drugs of rapamycin, while stability and in vitro
studies along with in vitro metabolism studies have shown that AP-23573
is not.
Recent review papers have covered in detail the available clinical results
with the mTOR inhibitors [151, 156]. Overall, the compounds are well tolerated
and may induce prolonged stable disease and increase time to progression
in a subset of cancer patients. In particular, promising activity has
been reported for CCI-779 in patients with mantle cell non-Hodgkin’s lymphoma
[151].
7
Other Medicinal Chemistry Approaches to Block the Survival Pathway
Although much of the drug discovery efforts have been directed to modulate
the enzymatic activity of the different components of the survival pathway,
other therapeutic modes have been successfully explored for pathway interruption.
Some of these alternative medicinal chemistry approaches are briefly
reviewed in this section.
7.1
Phosphatidylinositol Analogues
Phosphatidylinositol lipid analogues, which are structurally similar to the
products of PI3Ks, have been designed and synthesized to interact with
PH domains and disrupt the activation of the PI3K/PKB pathway in tumor
cells. A representative example of this class of inhibitors is D-3-deoxyphosphatidyl-myo-inositol
ether lipid (DPIEL, compound 35, Fig. 7) [157].
This compound specifically binds to the PH domain of PKB, blocking the
translocation of this protein from the cytoplasm to the plasma membrane and
thus preventing PKB phosphorylation and activation (IC 50 =1.5± 0.3 µM).
DPIEL inhibits the proliferation of MCF-7 and HT29 tumor cell lines with
IC 50 values of 7.2 and 2.1 µM, respectively. Replacement of the phosphate
linkageofDPIELwithacarbamategrouporvaryingthenatureofthelipid
groups on the diacylglycerol-like side chain of DPIEL resulted in derivatives
that were less potent than the parent compound at inhibiting PKB in cells
(18- to 8-fold) and also less specific for the PH domain of PKB. In addition