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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
About Azenosertib
Azenosertib 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.
Posted In: ZNTL
