Other Presentations at AACR Highlight Progress in SuperGen's
Oncology-Focused Pre-Clinical Pipeline
LOS ANGELES, April 19 /PRNewswire-FirstCall/ -- SuperGen Inc. (Nasdaq:
SUPG) today announced that MP470, its multi-targeted tyrosine kinase
inhibitor, suppresses the Rad51 protein, a critical component of double-
stranded DNA repair in cancer cells as part of a series of presentations at
the 2007 American Association for Cancer Research Annual Meeting (Abstract
4028).
Additional research findings presented by SuperGen scientists and their
collaborators included data pertaining to the improved bioavailability and
tolerability of the hydrochloride salt of MP470 as compared to the free
base (Abstract 1540). Two posters also demonstrated the use of SuperGen's
proprietary CLIMB technology and drug discovery process to facilitate lead
development and the design of several novel small molecule inhibitors,
including Axl kinase (Abstract 2380), as well as inhibitors of Jak2
(Abstract 2387).
The company also presented new animal model studies for small molecule
inhibitors of DNMT1 in zebrafish (Abstract 2229), data from its preclinical
compound MP529, a selective Aurora A kinase inhibitor (Abstract 3261) and
new data exhibiting receptor tyrosine kinase inhibition in combination with
an inhibitor of EGFR in mouse xenograft models (Abstract 5421). Finally, a
mini- symposium was presented about work conducted at The Ohio State
University on SuperGen's novel DNA hypomethylating agents that selectively
induced degradation of DNMT1 in human cancer cells (Abstract 4142).
Copies of the poster presentations will be available in the pipeline
section of SuperGen's Web site http://www.supergen.com.
"We are very encouraged by the strength of the preclinical data from
our drug discovery and development programs and are awaiting the initiation
of the Phase 1 clinical trial of MP470," said Dr. James S. Manuso,
SuperGen's Chairman, President and Chief Executive Officer. "Our products
and programs were highlighted in seven posters and a mini-symposium. The
data presented brings to light important new aspects of our late-stage
preclinical compounds and also validates CLIMB as a rapid and powerful
process for the identification of a broad range of potent small molecule
inhibitors."
Abstract No. 4028
MP470, a potent suppressor of Rad51, improves response to
platinum-based anticancer agents
Rad51 is an important protein involved in resistance to cytotoxic/DNA
damaging therapies that are commonly used to treat tumors. It acts to
repair the double stranded DNA breaks that are caused by therapies, thus
limiting their efficacy and increasing dosage requirements. Data indicate
that SuperGen's novel compound, MP470, blocks the induction of Rad51 by
anticancer platinum agents. MP470, in combination with carboplatin and
paclitaxel in small cell and non-small cell lung cancer lines, showed a
significant improvement in tumor response over the carboplatin/paclitaxel
treatments alone. A combination therapy regimen that includes MP470 in
addition to a platinum-based cytotoxic agent could reduce dosage
requirements and widen the therapeutic window.
Abstract No. 1540
Hydrochloride salt of MP470, a potent suppressor of Rad51, improves
bioavailability and tolerability
Results from this study suggest that the hydrochloride salt of MP470
(MP470.HCl) could lead to improved safety and tolerability of the compound.
Data indicate that MP470.HCl exhibits a several-fold improvement in oral
bioavailability when compared to the free base. The compound had a wide
therapeutic window in rat and dog models. Additionally, no apparent serious
toxicities in the expected therapeutic dose range were observed.
Abstract No. 2380
Discovery and characterization of a series of Axl kinase inhibitors
using the CLIMB process
Using CLIMB, researchers created a model of Axl kinase to screen a
large virtual library of chemical structures from which five chemical lead
scaffolds were selected. Structural modifications improved biochemical and
cell-based potency that resulted in compounds that exhibit sensitization to
apoptosis and down regulation of Axl-dependent signaling pathways.
Inhibitor SGI-AXL-277, a pyrrolopyrimidine, demonstrated low micromolar
activity against the Axl enzyme and in cell proliferation assays. Lead
optimization toward the identification of a clinical candidate is ongoing.
Abstract No. 2387
Discovery and characterization of small molecule inhibitors for Jak2
Janus kinases (JAKs) are critical to a number of intracellular
signaling pathways. Failure of Jak2 regulation or mutations that activate
Jak2 expression are implicated in leukemias, lymphomas and various solid
tumors. Utilizing CLIMB, researchers used a Jak2 crystal structure to build
several models that were made into a substrate for screening a large,
virtual small molecule library. This process generated a subset of leads
based on calculated binding energies. These leads were then screened in
silico to determine "druggable" candidates. Cell-based activity was
determined in HEL, K562, MO7 and other human cancer cell lines.
Abstract No. 2229
Zebrafish as a model mechanistic screen for small molecule inhibitors
of DNMT1
Data suggest that the zebrafish model offers a fast and reliable method
to identify small molecule inhibitors of DNA methyltransferase (DNMT).
DNMT1 is considered to be the DNA methyltransferase enzyme mainly
responsible for maintaining abnormal promoter methylation in various cancer
types. Zebrafish embryos are a viable model for cancer drug research
because of their close similarity to humans and their fast and easily
visible development. Small molecules that inhibit DNMT1 should produce
terminal differentiation abnormalities of the gut tube, retina and exocrine
pancreas, all of which are easily visualized. This screen allows quick
validation of DNMT1 inhibition in vivo, as well as important data on the
toxicity of compounds tested.
Abstract No. 3261
Discovery and development of MP529, a new effective and selective
inhibitor of Aurora A kinase
MP529 series compounds, such as SGI-498, SGI-503, SGI-1097 and
SGI-1215, demonstrate potent nanomolar inhibitory activity against the
Aurora-A enzyme in biochemical enzyme-based assays, while exhibiting little
to no activity versus the Aurora B kinase. SuperGen developed this series
of lead compounds for use in anticancer therapy using rational-based drug
design. Extensive in silico screening reduced the number of compounds
submitted to physical assays to fewer than 100, saving significant time and
resources over standard drug discovery practices. The series of compounds
was evaluated in in vivo xenograft models and showed efficacy while
maintaining desirable pharmacokinetic properties.
Abstract No. 5421
Dual inhibition of receptor tyrosine kinases of PDGFR and EGFR
abolishes prostate cancer cell growth in culture and in a mouse xenograft
model by complete dephosphorylation of PKB/Akt
MP470, SuperGen's multi-targeted tyrosine kinase inhibitor, in
combination with Tarceva was more effective than either treatment alone in
the inhibition of cell proliferation and phosphorylation of Akt in EGF and
PDGF pathways. Moreover, in combination with Tarceva, MP470 inhibited Akt
phosphorylation in LNCaP prostate cells. Finally, the MP470/Tarceva
treatment was shown to abolish prostate tumor growth in an LNCaP xenograft
mouse model
Mini-symposium Abstract No. 4142
Novel DNA hypomethylating agents: non-nucleoside compounds that do not
incorporate into DNA selectively induce degradation of DNA
methyltransferase I (DNMT1) in human cancer cells by the proteasomal
pathway and re-express silenced tumor suppressor genes
Researchers have discovered a novel class of quinoline-based compounds
that are not incorporated into DNA and cause selective degradation of DNMT1
in human cancer cells with minimal or no effects on DNMT3A and DNMT3B that
have been discovered. This addresses an issue with re-activation of
silenced tumor suppressor genes by 5-Azacytidine (5-AzaC or Vidaza) and its
congener 5-aza- deoxycydinite (5-aza-CdR or Decitabine or Dacogen). These
compounds provide a different mechanistic approach to the creation of
cancer therapies because they selectively and rapidly induce degradation of
maintenance DNA methyltransferase, DMNT1. However, they show some toxicity
due to their incorporation into the cell DNA. One compound in particular,
S1027, resulted in complete degradation of DNMT1 within 24 hours of
treatments and also blocked degradation as a pre-treatment of cells with
proteasomal inhibitors.
About SuperGen
Based in Dublin, Calif., SuperGen is a pharmaceutical company dedicated
to the discovery, rapid development and commercialization of therapies for
solid tumors and hematological malignancies. SuperGen is developing a
number of therapeutic anticancer products focused on inhibitors of
aurora-A, tyrosine kinase and DNA methyltransferase. For more information
about SuperGen, please visit http://www.supergen.com.
This press release contains "forward-looking" statements within the
meaning of Section 21A of the Securities Act of 1933, as amended, and
Section 21E of the Securities Exchange Act of 1934, as amended, and is
subject to the safe harbor created thereby. The actual results could differ
materially from those projected in the forward-looking statements as a
result of a number of risks and uncertainties. These forward-looking
statements include statements regarding the ability of our products to
enter clinical trials and the potential validation of our discovery process
to produce new compounds. SuperGen's products may not enter clinical trials
and even if these products do enter clinical testing there is no assurance
that these tests will be successful. Additionally, the early successes in
preclinical work may not be a validation of our discovery process and past
success may not predict future success. Other factors that could cause
actual results to differ materially from expectations include, but are not
limited to, the risk factors detailed in the Company's filings with the
Securities and Exchange Commission including reports on its most recently
filed Form 10-K. These forward-looking statements are made only as of the
date hereof, and we disclaim any obligation to update or revise the
information contained in any such forward-looking statements, whether as a
result of new information, future events or otherwise.
Contacts:
SuperGen Noonan Russo
Timothy L. Enns Greg Geissman
S.V.P., Corporate Communications Director of Media Relations
& Business Development
(925) 560-0100 x111 (619) 814-3511
tenns@supergen.com greg.geissman@eurorscg.com
SOURCE SuperGen Inc.
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Related links:
http://www.supergen.com
CONTACT:
Timothy L. Enns, S.V.P., Corporate
Communications & Business Development, of SuperGen,
+1-925-560-0100 x111, tenns@supergen.com; or Greg Geissman,
Director of Media Relations, Noonan Russo, +1-619-814-3511,
greg.geissman@eurorscg.com, for SuperGen Inc.
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