Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90

Although therapeutically targeting a single signaling pathway that
drives tumor development and/or progression has been effective for a
number of cancers, in many cases this approach has not been successful.
Targeting networks of signaling pathways, instead of isolated pathways,
may overcome this problem, which is probably due to the extreme
heterogeneity of human tumors. However, the possibility that such
networks may be spatially arranged in specialized subcellular
compartments is not often considered in pathway-oriented drug discovery
and may influence the design of new agents. Hsp90 is a chaperone protein
that controls the folding of proteins in multiple signaling networks
that drive tumor development and progression. Here, we report the
synthesis and properties of Gamitrinibs, a class of small molecules
designed to selectively target Hsp90 in human tumor mitochondria.
Gamitrinibs were shown to accumulate in the mitochondria of human tumor
cell fines and to inhibit Hsp90 activity by acting as ATPase
antagonists. Unlike Hsp90 antagonists not targeted to mitochondria,
Gamitrinibs exhibited a ``mitochondriotoxic'' mechanism of action,
causing rapid tumor cell death and inhibiting the growth of xenografted
human tumor cell lines in mice. Importantly, Gamitrinibs were not toxic
to normal cells or tissues and did not affect Hsp90 homeostasis in
cellular compartments other than mitochondria. Therefore, combinatorial
drug design, whereby inhibitors of signaling networks are targeted to
specific subcellular compartments, may generate effective anticancer
drugs with novel mechanisms of action.