Zentalis Pharmaceuticals to Present Azenosertib Preclinical Data at ESMO 2024

Zentalis Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company focused on developing small molecule therapeutics for cancer treatment, has announced the presentation of preclinical data on its selective WEE1 inhibitor, azenosertib. The data will be showcased at the European Society of Medical Oncology (ESMO) 2024 Congress in Barcelona, Spain, scheduled for September 13-17.

Azenosertib, Zentalis' proprietary WEE1 inhibitor, has shown significant promise in combination with topoisomerase I (TOP1) inhibitor-based antibody-drug conjugates (ADCs). This combination has demonstrated synergistic anti-tumor effects in various preclinical models. The company's Chief Scientific Officer, Dr. Mark Lackner, emphasized the potential of combining azenosertib with ADCs, stating that the integration of DNA damage induced by TOP1 inhibitors with the cell cycle deregulation caused by azenosertib provides a strong mechanistic basis for their synergistic effects.

The data to be presented at ESMO includes findings from several preclinical experiments. Notably, in HER2-positive breast cancer animal models, combining azenosertib with trastuzumab deruxtecan (T-Dxd) resulted in a 50% complete tumor regression rate, a significant improvement over monotherapy treatments. Similar positive outcomes were observed in HER2-positive ovarian and HER2-low breast cancer models. These results indicate that azenosertib can substantially enhance the efficacy of TOP1 inhibitors and ADCs with TOP1 inhibitor payloads, potentially offering a new therapeutic approach for patients with advanced solid tumors.

Azenosertib is an oral WEE1 inhibitor that is currently in clinical trials both as a standalone treatment and in combination with other therapies for ovarian cancer and other tumor types. WEE1 plays a critical role in regulating the G1-S and G2-M cell cycle checkpoints by negatively influencing CDK1 and CDK2 to prevent the replication of DNA-damaged cells. By inhibiting WEE1, azenosertib disrupts this regulation, allowing cell cycle progression despite DNA damage, ultimately leading to cancer cell death through mitotic catastrophe.

Zentalis Pharmaceuticals is committed to advancing azenosertib through clinical development. The company is also exploring specific enrichment strategies targeting tumors with high genomic instability, such as Cyclin E1 positive tumors, homologous recombination deficient tumors, and tumors with specific oncogenic mutations. In addition, Zentalis is utilizing its expertise in cancer biology and medicinal chemistry to further research on protein degraders.

Headquartered in San Diego, Zentalis Pharmaceuticals continues to push the boundaries in cancer treatment by focusing on small molecule therapeutics that target fundamental biological pathways in cancer. The company’s leading candidate, azenosertib, has shown promise as a first-in-class and best-in-class WEE1 inhibitor for treating advanced solid tumors and hematologic malignancies. Clinical trials have indicated that azenosertib is well tolerated and effective as a monotherapy and in combination with various chemotherapy regimens.

As Zentalis progresses with its clinical development programs, the combination of azenosertib with ADCs that utilize TOP1 inhibitors could become a transformative treatment strategy for patients with advanced solid tumors, offering new hope where traditional therapies may have fallen short.