Copper redox reaction key to elesclomol's ability to generate ROS
LEXINGTON, Mass.--(BUSINESS WIRE)--Nov. 18, 2009--
Synta Pharmaceuticals Corp. (NASDAQ: SNTA), a biopharmaceutical company
focused on discovering, developing, and commercializing small molecule
drugs to treat severe medical conditions, today presented new data on
the mechanism of action of elesclomol, a first-in-class oxidative stress
inducer, at the AACR-NCI-EORTC Conference on Molecular Targets and
Cancer Therapeutics in Boston, Mass.
“Elesclomol has been shown previously to induce apoptosis in cancer
cells by increasing the level of reactive oxygen species (ROS),” said
Vojo Vukovic M.D., Ph.D., Chief Medical Officer, Synta Pharmaceuticals.
“The results presented today provide new details on the underlying
mechanism by which elesclomol elevates oxidative stress. Elesclomol
binds copper in plasma, facilitates its uptake into cells, and enables a
transition between copper oxidation states once inside the cell. These
results also point towards the origin of elesclomol’s unusual
cancer-cell selectivity – its ability to kill cancer cells with little
to no effect on normal cells. Cancer cells and normal cells are well
known to have distinct metabolic properties, including the
electrochemical properties of the mitochondria where many of these redox
reactions take place. Taking advantage of these metabolic and
electrochemical differences represents an entirely new and exciting
approach, distinct from kinase inhibition or conventional chemotherapy,
to selectively target and kill cancer cells. These unique properties of
elesclomol are important considerations for future clinical
applications. Additional results related to the elesclomol mechanism of
action and hematologic applications will be presented at the American
Society of Hematology meeting next month.”
The results of the in vitro studies demonstrated that:
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Elesclomol binds to copper as Cu(II) outside the cell
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The chelation of copper facilitates the entry of elesclomol into the
cell
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Once in the cell, elesclomol promotes a reduction reaction where
Cu(II) transitions to Cu(I)
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The redox reaction leads to the generation of reactive oxygen species
(ROS)
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This process is necessary for elesclomol’s anticancer activity
(ability to induce oxidative stress to the point of apoptosis).
About Elesclomol
Elesclomol is a first-in-class oxidative stress inducer that triggers
apoptosis (programmed cell death) in cancer cells. Cancer cells operate
at high level of oxidative stress, marked by an elevated presence of
reactive oxygen species (ROS) such as oxygen radicals and hydrogen
peroxide. In laboratory studies, elesclomol has been observed to
increase the level of ROS in cancer cells even further, leading to an
increase in pro-apoptotic factors, a decrease in anti-apoptotic factors,
the opening of the mitochondrial membrane pores, and ultimately to the
initiation of programmed cell death via the mitochondrial apoptosis
pathway. This mechanism of action, called oxidative stress induction,
represents a novel way of selectively targeting and killing cancer cells.
In preclinical models elesclomol showed potent anti-cancer activity
against a broad range of cancer cell types, as well as an ability to
enhance the efficacy of certain chemotherapy agents with minimal
additional toxicity. In a 21-center, double-blind, randomized,
controlled Phase 2b clinical trial in 81 patients with metastatic
melanoma, elesclomol in combination with paclitaxel achieved the primary
endpoint of improvement in progression-free survival compared to
paclitaxel alone. The subsequent Phase 3 trial in 650 patients with
metastatic melanoma, the SYMMETRY trial, was suspended in February 2009,
based on an interim analysis that identified possible safety concerns.
Preliminary results from the SYMMETRY trial were presented at ASCO in
May 2009 and Perspectives in Melanoma XIII in October 2009, showing a
differential response to treatment with elesclomol based on level of
baseline LDH. Clinical trials with elesclomol remain on hold pending
further review of the SYMMETRY trial results. Further results related to
elesclomol, including survival data from the SYMMETRY trial with one
year minimum follow-up, will be presented in the first half of 2010.
About Synta Pharmaceuticals
Synta Pharmaceuticals Corp. is a biopharmaceutical company focused on
discovering, developing, and commercializing small molecule drugs to
extend and enhance the lives of patients with severe medical conditions,
including cancer and chronic inflammatory diseases. Synta has a unique
chemical compound library, an integrated discovery engine, and a diverse
pipeline of clinical- and preclinical-stage drug candidates with
distinct mechanisms of action and novel chemical structures. All Synta
drug candidates were invented by Synta scientists using our compound
library and discovery capabilities. For more information, please visit www.syntapharma.com.
Safe Harbor Statement
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Source: Synta Pharmaceuticals Corp.
Synta Pharmaceuticals Corp.
Rob Kloppenburg, 781-541-7125