Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) today announced that
two posters detailing preclinical data from its BTK and PDK1
inhibitor programs were presented on Sunday, November 8th at the
AACR-NCI-EORTC International Conference on Molecular Targets and
Cancer Therapeutics being held in Boston, Massachusetts.
The two poster presentations (Abstracts C198 and C186), titled
"SNS-062 is a potent noncovalent BTK inhibitor with comparable
activity against wild type BTK and BTK with an acquired resistance
mutation" and "PDK1 inhibitors SNS-229 and SNS-510 cause pathway
modulation, apoptosis and tumor regression in hematologic cancer
models in addition to solid tumors," are available on the Sunesis
website at www.sunesis.com.
"These data represent the first peer-reviewed presentations by
Sunesis of our two proprietary kinase inhibitor pipeline programs,"
said Dan Swisher, Chief Executive Officer of Sunesis. "Each shows
compelling, anti-cancer activity and a distinct product profile.
SNS-062, our novel, second-generation BTK inhibitor, maintains
potent preclinical activity in the presence of a cysteine-481
mutation associated with acquired resistance to ibrutinib. In
addition, SNS-062 has a kinase selectivity profile distinct from
ibrutinib that may confer additional safety and efficacy advantages
that we look forward to uncovering in our upcoming clinical
studies. SNS-510 and SNS-229, which belong to a novel class of PDK1
kinase inhibitors, show broad activity in a variety of hematologic
cancer cell lines, including cell lines resistant to PI3K and AKT
inhibitors, that correlates with significant PDK1 pathway
modulation and anti-proliferative activity. We believe this program
could soon yield a first-in-clinic selective PDK1 inhibitor to test
this important pathway in cancer patients. Near term, we look
forward to advancing SNS-062 into the clinic in the first quarter
of 2016."
Study Results in Detail
"SNS-062 is a potent noncovalent BTK inhibitor with comparable
activity against wild type BTK and BTK with an acquired resistance
mutation"
For this study, Sunesis researchers explored the potential of
SNS-062, a potent, noncovalent BTK inhibitor, to overcome
resistance mechanisms of ibrutinib, a BTK inhibitor with validated
anti-cancer efficacy in several B-cell malignancies. These
resistance mechanisms include mutation of the cysteine in the BTK
active site that ibrutinib requires for covalent binding (C481).
SNS-062 has a kinase selectivity profile distinct from ibrutinib
showing nM binding affinity for BTK, ITK and Tec kinase family
members, but does not meaningfully bind EGFR. A lack of EGFR
inhibition by SNS-062 may offer safety advantages over ibrutinib,
including reduced diarrhea and rash potentially related to
inhibition of EGFR.
Prolonged SNS-062 mediated in vivo inhibition of BTK correlates
with potent anti-inflammatory activity in a BTK dependent B-cell
mediated collagen induced rat arthritis model. To assess the
activity of SNS-062 and ibrutinib against BTK with acquired
resistance mutations, inhibition of wild type (WT) and mutant C481S
BTK was evaluated in direct kinase assays. SNS-062 inhibits WT and
C481S BTK with similar inhibitory concentrations while ibrutinib
potency is reduced 40 fold. Similarly, ibrutinib shows a 100 fold
loss of potency in inhibiting pBTK levels in C481S BTK expressing
cells while SNS-062 activity is unaffected.
SNS-062 shows good oral bioavailability in multiple animal
species with a terminal half-life of three to six hours.
Pharmacokinetic, pharmacodynamic and toxicity studies demonstrate
that SNS-062 plasma concentrations providing >90% inhibition of
BTK can be sustained with acceptable tolerability.
"PDK1 inhibitors SNS-229 and SNS-510 cause pathway modulation,
apoptosis and tumor regression in hematologic cancer models in
addition to solid tumors"
Phosphatidylinositol (PI) dependent kinase 1, or PDK1, is a
master kinase that activates kinases important in cell growth and
survival including members of the AKT, PKC, RSK and SGK families
and can interact with its substrates through PI-dependent
(PH-mediated) or PI-independent (PIF-mediated) mechanisms. For this
study, Sunesis researchers characterized two potent PDK1 kinase
inhibitors, SNS-229 and SNS-510, with broad preclinical antitumor
activity in hematologic cancers.
SNS-229 and SNS-510 belong to a novel class of PDK1 inhibitors
that bind the inactive conformation of PDK1 as determined by X-ray
crystallography and induce a conformational change that perturbs
the PIF-pocket, thereby inhibiting PIF-mediated substrate binding,
in contrast to the ATP-competitive PDK1 inhibitor tool compounds
GSK2334470 and BX-320.
SNS-229 and SNS-510 were evaluated in more than twenty cell
lines derived from hematologic cancers including acute myeloid
leukemia, multiple myeloma, B-cell lymphoma, and mantle cell
lymphoma. SNS-510 shows strong anti-proliferative activity and
induces apoptosis in PI3K and AKT inhibitor resistant cell lines.
SNS-229 and SNS-510 are compared to the PDK1 inhibitor GSK2334470
and were up to 30 fold more potent at inhibiting PDK1, S6K, RSK and
AKT phosphorylation and up to 50 fold more potent in cancer cell
viability assays.
In vivo, SNS-510 shows dose and time dependent inhibition of
PDK1 autophosphorylation and up to 90% inhibition of RSK2 and AKT
phosphorylation after eight hours, whereas GSK-2334470 and the
pan-PI3K inhibitor GDC0941 only show moderate PDK1 and RSK2
inhibition and no AKT inhibition. In PK studies in CD/1 mice,
SNS-229 and SNS-510 have good pharmacokinetic properties, with a
terminal half-life of four to five hours and an oral
bioavailability of >90%.
In an AML xenograft mouse model, both SNS-229 and SNS-510 show
dose-related efficacy with >95% tumor growth inhibition and
partial regression (>50% tumor shrinkage) in 70% and 100% of
animals at the highest dose after 21-day dosing. These studies show
that targeting the inactive conformation of PDK1 leads to potent
and sustained pathway inhibition resulting in strong tumor growth
inhibition and regression.
About Sunesis Pharmaceuticals
Sunesis is a biopharmaceutical company focused on the
development and commercialization of new oncology therapeutics for
the potential treatment of solid and hematologic cancers. Sunesis
has built a highly experienced cancer drug development organization
committed to advancing its lead product candidate, vosaroxin, in
multiple indications to improve the lives of people with
cancer.
For additional information on Sunesis, please
visit http://www.sunesis.com.
SUNESIS and the logos are trademarks of Sunesis
Pharmaceuticals, Inc.
This press release contains forward-looking statements,
including statements related to Sunesis' expected progress in its
kinase inhibitor pipeline. Words such as "may," "expect,"
"intends," "plan," "potential," "will" and similar expressions are
intended to identify forward-looking statements. These
forward-looking statements are based upon Sunesis' current
expectations. Forward-looking statements involve risks and
uncertainties. Sunesis' actual results and the timing of events
could differ materially from those anticipated in such
forward-looking statements as a result of these risks and
uncertainties, which include, without limitation, the risk that
Sunesis' clinical studies for its product candidates may not
demonstrate safety or efficacy or lead to regulatory approval, the
risk that data to date and trends may not be predictive of future
data or results, risks related to the conduct of Sunesis' clinical
trials, risks related to Sunesis' need for substantial additional
funding to complete the development and commercialization of
vosaroxin, and risks related to Sunesis' ability to raise the
capital that it believes to be accessible and is required to fully
finance the development and commercialization of vosaroxin. These
and other risk factors are discussed under "Risk Factors" and
elsewhere in Sunesis' Quarterly Report on Form 10-Q for the quarter
ended September 30, 2015. Sunesis expressly disclaims any
obligation or undertaking to release publicly any updates or
revisions to any forward-looking statements contained herein to
reflect any change in Sunesis' expectations with regard thereto or
any change in events, conditions or circumstances on which any such
statements are based.
CONTACT: Investor and Media Inquiries:
David Pitts
Argot Partners
212-600-1902
Eric Bjerkholt
Sunesis Pharmaceuticals Inc.
650-266-3717
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