Novel Synta Hsp90 inhibitor shows up to 100x greater potency and reduced toxicity relative to 17-AAG in both in vitro and in vivo models
STA-9090 shows activity in models resistant to 17-AAG
LEXINGTON, Mass.--(BUSINESS WIRE)--Apr. 21, 2009--
Synta Pharmaceuticals Corp. (NASDAQ: SNTA), a biopharmaceutical company
focused on discovering, developing, and commercializing small molecule
drugs to treat severe medical conditions, today announced that
preclinical data presented at the annual meeting of the American
Association for Cancer Research (AACR) shows that STA-9090, a novel,
synthetic inhibitor of heat shock protein 90 (Hsp90), demonstrated
greater activity in lung cancer cells when compared to the 17-AAG class
of Hsp90 inhibitors, the class most advanced in the clinic.
“The results presented today from the preclinical experiments performed
at Dr. Geoffrey Shapiro’s lab at the Dana-Farber Cancer Institute
provide compelling evidence that STA-9090 may have substantial and
important advantages over the first generation of Hsp90 inhibitors, such
as 17-AAG,” said Jim Barsoum Ph.D., Senior Vice President, Research,
Synta Pharmaceuticals. “Inhibition of Hsp90 is an area of great interest
in the oncology community because of the broad role played by Hsp90 in
maintaining the function of many cancer-promoting proteins. The results
presented today highlight the effectiveness of STA-9090 in lung cancer,
including lung cancers resistant to Tarceva. This activity against
cancers resistant to a kinase inhibitor is consistent with the
underlying rationale of targeting the Hsp90 chaperone protein rather
than the kinase itself. Along with work presented by Dr. Shapiro’s lab,
we and our collaborators have shown broad activity of STA-9090 against
multiple cancer types, including both cancers that are sensitive to
kinase inhibitors, such as Gleevec and Sutent, and cancers that are
resistant to those kinase inhibitors. These collective results have
shown that STA-9090 is differentiated within the Hsp90 inhibitor class,
including improved potency and reduced toxicity compared to the 17-AAG
family of inhibitors.”
“In addition to our three on-going clinical trials of STA-9090, we are
excited to advance this program in the clinic. We are pleased by the
enthusiasm from the scientific and medical community for this program
and plan to initiate trials in a range of new cancer types later this
year,” continued Dr. Barsoum.
STA-9090 is an example of the ability of Synta to continue to generate
novel, best-in-class drug candidates using its discovery platform and
unique compound library of diverse, proprietary chemical structures.
Synta has five drug candidate programs in preclinical or clinical
development each representing distinct mechanisms of action, chemical
structures, and market opportunities. All programs have been discovered
and developed internally.
The Hsp90 data, presented in a poster by Takeshi Shimamura, Ph.D. and
Geoffrey Shapiro, M.D., Ph.D., of the Dana-Farber Cancer Institute,
showed that, depending on the experimental model, STA-9090 was up to 100
times more potent than the geldanamycin inhibitor 17-AAG in both in
vitro and in vivo models in non-small cell (NSCLC).
Additional findings demonstrated that:
STA-9090 inhibited proliferation and induced apoptosis in a large
panel of NSCLC cell lines with a more than four–fold greater potency
STA-9090 displayed activity against cell lines expressing seventeen
different epidermal growth factor receptor (EGFR) mutations commonly
found in NSCLC patients, including ten mutations that conferred
resistance to the EGFR inhibitor erlotinib (Tarceva).
STA-9090 induced depletion of Hsp90 clients such as AKT, EGFR, ERBB4,
IGF-1R, c-MET, PDGFRα, and c-RET a 3 to 9-fold lower drug
concentrations than for 17-AAG.
STA-9090 retained activity against lung cancer cell lines that were
resistant to treatment with 17-AAG.
STA-9090 showed greater efficacy and an increased therapeutic index
relative to 17-AAG in mouse models of Tarceva-resistant NSCLC.
It is estimated that 215,020 men and women (114,690 men and 100,330
women) in the United States were diagnosed with and 161,840 men and
women died of cancer of the lung and bronchus in 20081.
STA-9090 is currently being studied in two Phase 1 solid tumor clinical
trials and one Phase 1/2 trial in hematologic cancers. Synta has
announced that a second Phase 2 hematologic cancer trial will be started
Additional Abstracts Presented at AACR
Also presented at AACR was a poster by Xiaojiang Cui, Ph.D., of
the John Wayne Cancer Institute, which concluded that combining
elesclomol with the cytotoxic chemotherapeutic agents doxorubicin and
paclitaxel induced apoptosis in breast cancer cells. Activation of c-Jun
N-terminal kinase (JNK) signaling and downregulation of survival
proteins appeared to play a role in the induction of apoptosis. In
addition, Akt/Hsp70 survival signaling was also strongly induced by
elesclomol. Blockade of Akt activation using a small molecule inhibitor
enhanced elesclomol-elicited apoptosis.
In preclinical studies, STA-9090 has shown the ability to inhibit
multiple kinases with comparable potency to, and a broader activity
profile than specific kinase inhibitors such as imatinib, erlotinib, and
sunitinib. In addition, STA-9090 has shown potency 10 to 100 times
greater than the ansamycin family of Hsp90 inhibitors such as 17-AAG, as
well as activity against a wider range of kinases. In in vivo
models, STA-9090 has shown strong efficacy in a wide range of cancer
types, including cancers resistant to Gleevec and Tarceva.
Hsp90 is an emerging therapeutic target of interest for the treatment of
cancer. It is responsible for the maturation and function of numerous
signaling proteins – known as ‘client proteins’ – that are associated
with cancer cell survival and proliferation. Many cancers result from
specific mutations in, or aberrant expression of, these client proteins.
Examples of cancer-associated client proteins of Hsp90 include c-KIT in
gastrointestinal stromal tumors, epidermal growth factor receptor (EGFR)
in lung cancer, and BCR-ABL in chronic myelogenous leukemia. In
preclinical studies, inhibiting Hsp90 causes the degradation of these
proteins and cancer cell death. Inhibiting Hsp90 has also proven
effective in killing cancer cells that have developed resistance to
targeted therapies such as kinase inhibitors.
Elesclomol is a novel, injectable, investigational drug candidate that
triggers apoptosis (programmed cell death) in cancer cells. Cancer cells
operate at high levels of reactive oxygen species, or oxidative stress.
Elesclomol is believed to act by increasing the level of oxidative
stress in cancer cells even further, beyond sustainable levels, inducing
apoptosis. This mechanism of action, called oxidative stress induction,
represents a novel way of selectively targeting and killing cancer
cells. Clinical trials of elesclomol are on hold pending further
analysis of the full results of the Phase 3 (SYMMETRY) trial.
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.
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1. NCI SEER database, 2009 http://seer.cancer.gov/statfacts/html/lungb.html
Source: Synta Pharmaceuticals Corp.
Synta Pharmaceuticals Corp.
Rob Kloppenburg, 781-541-7125