Zentalis Pharmaceuticals to Highlight Preclinical Data Demonstrating that WEE1 Inhibitor Azenosertib Exerts Synergistic Anti-tumor Activity with KRAS(G12C) Inhibitors at AACR Annual Meeting 2024
April 02 2024 - 4:05PM
Zentalis® Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage
biopharmaceutical company discovering and developing clinically
differentiated small molecule therapeutics targeting fundamental
biological pathways of cancers, will present a poster with new
preclinical data at the 2024 Annual Meeting of the American
Association for Cancer Research (AACR) taking place in San Diego
April 5-10, 2024. Research demonstrated that the Company’s WEE1
inhibitor, azenosertib, exerts synergistic anti-tumor activity when
combined with KRASG12C inhibitors.
"As we advance azenosertib in multiple ongoing clinical studies,
our understanding of its potential utility as a monotherapy and in
combination across diverse tumor types and treatment settings
continues to deepen,” said Mark Lackner, Ph.D., Chief Scientific
Officer of Zentalis. “By exploiting azenosertib’s mechanism, which
targets common vulnerabilities related to cancer cell cycle
dysregulation and high levels of replication stress and DNA damage,
we sought to evaluate the anti-tumor activity of azenosertib in
KRAS-driven cancers when combined with KRASG12C inhibitors. Our
preclinical data demonstrate that combining azenosertib with
KRASG12C inhibitors dramatically enhances anti-tumor activity. This
compelling approach warrants further investigation as a potential
treatment option for patients with KRASG12C tumors.”
Azenosertib is a potent and selective inhibitor of WEE1, a
master cell cycle regulator that acts to slow cell cycle
progression and enable DNA repair. Inhibition of WEE1 by
azenosertib suppresses key cell cycle checkpoints, preventing DNA
repair and increasing DNA damage, resulting in mitotic catastrophe
and cell death. Previous research has determined that cancer cells,
which are often characterized by cell cycle dysregulation and high
levels of DNA damage, are highly sensitive to azenosertib. KRAS is
a potent oncogenic driver that results in unchecked cell cycle
progression while increasing replication stress and accumulation of
DNA damage.
The research that will be presented at AACR Annual Meeting 2024
evaluated the anti-tumor activity of azenosertib when administered
in combination with KRASG12C inhibitors sotorasib or adagrasib. The
data demonstrated synergistic cell growth inhibition across a panel
of KRASG12C cell lines in both 2D and 3D assays. Furthermore,
administration of azenosertib in KRASG12C inhibitor-sensitive and
resistant xenograft models, including using non-small cell lung
cancer, colorectal cancer, and pancreatic cancer cell lines,
demonstrated monotherapy activity as well as synergistic tumor
growth inhibition when combined with KRASG12C inhibitors. In
addition, extended administration of azenosertib combined with
KRASG12C inhibitors increased the duration of response versus
single agent use. Together, these results support continued study
of the potential for azenosertib to provide clinical benefit as a
combination therapy.Poster Presentation
Details
- Title: The selective WEE1 inhibitor
azenosertib shows synergistic anti-tumor activity with KRASG12C
inhibitors in multiple KRASG12C models
- Authors: Jameson, N.M. et al.
- Date/Time: Tuesday, April 9, 2023 at 1:30 pm -
5:00 pm PT
- Abstract Number: 6487
- Session: Targeting Kinase and ERK
Pathways
About AzenosertibAzenosertib is a novel,
selective, and orally bioavailable inhibitor of WEE1 currently
being evaluated as a monotherapy and combination clinical studies
in ovarian cancer and additional tumor types. WEE1 acts as a master
regulator of the G1-S and G2-M cell cycle checkpoints, through
negative regulation of both CDK1 and CDK2, to prevent replication
of cells with damaged DNA. By inhibiting WEE1, azenosertib enables
cell cycle progression, despite high levels of DNA damage, thereby
resulting in the accumulation of DNA damage and leading to mitotic
catastrophe and cancer cell death.
About Zentalis Pharmaceuticals
Zentalis® Pharmaceuticals, Inc. is a clinical-stage
biopharmaceutical company discovering and developing clinically
differentiated small molecule therapeutics targeting fundamental
biological pathways of cancers. The Company’s lead product
candidate, azenosertib (ZN-c3), is a potentially first-in-class and
best-in-class WEE1 inhibitor for advanced solid tumors and
hematologic malignancies. Azenosertib is being evaluated as a
monotherapy and in combination across multiple clinical trials and
has broad franchise potential. In clinical trials, azenosertib has
been well tolerated and has demonstrated anti-tumor activity as a
single agent across multiple tumor types and in combination with
several chemotherapy backbones. As part of its azenosertib clinical
development program, the Company is exploring enrichment strategies
targeting tumors of high genomic instability, such as Cyclin E1
positive tumors, homologous recombination deficient tumors and
tumors with oncogenic driver mutations. The Company is also
leveraging its extensive experience and capabilities across cancer
biology and medicinal chemistry to advance its research on protein
degraders. Zentalis has operations in both New York and San
Diego.
For more information, please visit www.zentalis.com. Follow
Zentalis on X/Twitter at @ZentalisP and on LinkedIn
at www.linkedin.com/company/zentalis-pharmaceuticals.
Forward-Looking StatementsThis press release
contains forward-looking statements within the meaning of the U.S.
Private Securities Litigation Reform Act of 1995. All statements
contained in this press release that do not relate to matters of
historical fact should be considered forward-looking statements,
including statements regarding the potential benefits of combining
azenosertib with KRAS targeted therapies; the potential benefits of
azenosertib as a monotherapy and in combination; the potential for
azenosertib to be best-in-class and first-in-class; the franchise
potential of azenosertib. The terms “potential,” “will” and similar
references are intended to identify forward-looking statements,
although not all forward-looking statements contain these
identifying words. These statements are neither promises nor
guarantees, but involve known and unknown risks, uncertainties and
other important factors that may cause our actual results,
performance or achievements to be materially different from any
future results, performance or achievements expressed or implied by
the forward-looking statements, including, but not limited to, the
following: our limited operating history, which may make it
difficult to evaluate our current business and predict our future
success and viability; we have and expect to continue to incur
significant losses; our need for additional funding, which may not
be available; our plans, including the costs thereof, of
development of any diagnostic tools; our substantial dependence on
the success of our lead product candidates; the outcome of
preclinical testing and early trials may not be predictive of the
success of later clinical trials; failure to identify additional
product candidates and develop or commercialize marketable
products; potential unforeseen events during clinical trials could
cause delays or other adverse consequences; risks relating to the
regulatory approval process or ongoing regulatory obligations;
failure to obtain U.S. or international marketing approval; our
product candidates may cause serious adverse side effects;
inability to maintain our collaborations, or the failure of these
collaborations; our reliance on third parties; effects of
significant competition; the possibility of system failures or
security breaches; risks relating to intellectual property; our
ability to attract, retain and motivate qualified personnel, and
risks relating to management transitions; significant costs as a
result of operating as a public company; and the other important
factors discussed under the caption “Risk Factors” in our most
recently filed periodic report on Form 10-K or 10-Q and subsequent
filings with the U.S. Securities and Exchange Commission (SEC) and
our other filings with the SEC. Any such forward-looking statements
represent management’s estimates as of the date of this press
release. While we may elect to update such forward-looking
statements at some point in the future, we disclaim any obligation
to do so, even if subsequent events cause our views to change.
ZENTALIS® and its associated logo are trademarks of Zentalis
and/or its affiliates. All website addresses and other links in
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information into this press release.
Contact:Carlo Tanzi, Ph.D.Kendall Investor
Relationsctanzi@kendallir.com
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