A Comprehensive Report on Azenosertib (ZN-c3): A First-in-Class WEE1 Inhibitor for Oncologic Indications

Executive Summary

Azenosertib (also known as ZN-c3) is an investigational, orally bioavailable, small molecule drug being developed by Zentalis Pharmaceuticals as a potentially first-in-class and best-in-class inhibitor of WEE1 kinase. The primary mechanism of action involves the targeted inhibition of WEE1, a critical regulator of the G2/M cell cycle checkpoint. This inhibition abrogates the cell's ability to arrest and repair DNA damage before mitosis, leading to a cascade of events including increased replication stress, premature mitotic entry, and ultimately, cancer cell death via mitotic catastrophe. This therapeutic strategy is particularly effective in tumors characterized by high genomic instability, such as those with p53 mutations or, most notably, overexpression of Cyclin E1, which has emerged as a key predictive biomarker for Azenosertib sensitivity.

The clinical development program for Azenosertib is extensive, evaluating the agent as both a monotherapy and in combination with chemotherapy, PARP inhibitors, and other molecularly targeted agents across a range of solid tumors. The program's strategy has been significantly refined by pharmacokinetic studies that established an optimized intermittent dosing schedule (400 mg daily, 5 days on, 2 days off), which more than doubles drug exposure while improving tolerability compared to continuous dosing.