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Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90
Byoung Heon Kang, … , Len Neckers, Dario C. Altieri
Byoung Heon Kang, … , Len Neckers, Dario C. Altieri
Published February 23, 2009
Citation Information: J Clin Invest. 2009;119(3):454-464. https://doi.org/10.1172/JCI37613.
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Research Article

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

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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.

Authors

Byoung Heon Kang, Janet Plescia, Ho Young Song, Massimiliano Meli, Giorgio Colombo, Kristin Beebe, Bradley Scroggins, Len Neckers, Dario C. Altieri

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Figure 6

Selectivity of Gamitrinib anticancer activity.

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Selectivity of Gamitrinib anticancer activity.
(A) Mitochondrial membran...
(A) Mitochondrial membrane potential. TMRM-loaded mitochondria isolated from WS-1 normal human fibroblasts were incubated with Gamitrinib-G4 or 17-AAG plus the uncoupled mitochondriotropic moiety TG-OH and analyzed for changes in inner membrane potential in the presence or absence of CsA. (B) Cytochrome c release. Mitochondria isolated from normal HFF fibroblasts were treated with Gamitrinibs or 17-AAG and analyzed by Western blotting. HeLa cells were used as control. Cox-IV or Ran was used as a mitochondrial or cytosolic marker, respectively. Reactivity of the antibody to Ran with isolated cytosolic extracts from HeLa or HFF cells was used as a control. (C) Mitochondrial accumulation. Isolated normal mouse liver mitochondria were incubated with vehicle, 17-AAG, or Gamitrinib-G4 in the presence or absence of CsA and analyzed using absorbance. Data are the mean ± SEM. (D) Analysis of cell viability. Human fibroblasts (HFF, black line), bovine aortic endothelial cells (brown line), intestinal epithelial cells (red line), or human umbilical vein endothelial cells (green line) were treated with Gamitrinib-G4 (solid lines) or 17-AAG (dashed lines) and analyzed using MTT assay after 24 hours. Data are representative of 2 experiments.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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