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

Abstract

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 lines 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.

TRAP1 regulation of mitochondrial life or death decision in cancer cells and mitochondria-targeted TRAP1 inhibitors

“…This indicates that Hsp90-targeted drugs designed to occupy the ATP pocket in the Hsp90 N domain can also inhibit the TRAP1 chaperone function in vitro. The common Hsp90 inhibitors, however, cannot compromise the function of TRAP1 in vivo due to its mitochondrial location (16,17).…”

“…To make them reach the target proteins and directly induce MMP, it is required to use a drug delivery system targeted to the mitochondria. Gamitrinibs are the first mitochondria-targeted small molecules which inhibit TRAP1 and Hsp90 inside the mitochondria (17). Gamitrinibs directly induced MMP, resulting in loss of mitochondrial inner membrane potential and discharge of cytochrome c into the cytosol, followed by extensive cell death in many cancer cells (17,48,49).…”

“…Gamitrinibs are the first mitochondria-targeted small molecules which inhibit TRAP1 and Hsp90 inside the mitochondria (17). Gamitrinibs directly induced MMP, resulting in loss of mitochondrial inner membrane potential and discharge of cytochrome c into the cytosol, followed by extensive cell death in many cancer cells (17,48,49). Gamitrinibs are composed of 3 modules: 1) a mitochondrial targeting module, cyclic guanidinium or triphenylphosphonium, 2) the prototype Hsp90 inhibitor, geldanamycin, and 3) short linkers connecting between them (17).…”

“…Gamitrinibs have no effect on cytosolic Hsp90, and thereby neither change client expression nor induce heat shock responses. Meanwhile, CPP-containing inhibitors compromise the function of cytoplasmic Hsp90, which, as a result, elevates the expression of Hsp70 as a heat shock response and degrades client proteins (17). Gamitrinibs show much improved anticancer activity compared to the CPP-containing shepherdin and Ant-GA when they are used to treat cancer cell types in vitro or mouse tumor xenografts in vivo, probably due to the effective accumulation of the drugs in the target organelle mitochondria (16,17).…”

“…Meanwhile, CPP-containing inhibitors compromise the function of cytoplasmic Hsp90, which, as a result, elevates the expression of Hsp70 as a heat shock response and degrades client proteins (17). Gamitrinibs show much improved anticancer activity compared to the CPP-containing shepherdin and Ant-GA when they are used to treat cancer cell types in vitro or mouse tumor xenografts in vivo, probably due to the effective accumulation of the drugs in the target organelle mitochondria (16,17). Hence, when considering broad and selective cytotoxic activities in various cancer cells in vitro and in vivo, targeting the mitochondrial chaperone is a feasible strategy to develop a novel class of anticancer drugs such as Gamitrinibs, with potent anticancer activity and a unique mechanism of action (37,51).…”