Genomic instability and accumulation of DNA damage are hallmarks of tumor development and progression. To ensure the maintenance of genomic integrity, cells rely on a coordinated DNA damage response network that regulates cell-cycle progression, including activation of WEE1-dependent cell cycle checkpoints. If DNA damage occurs during replication, the WEE1 checkpoint is activated, thereby preventing the progression of the cell cycle. This allows damaged DNA to be repaired before cells enter mitosis, or if the damage is too extensive, induction of apoptosis. These observations have made WEE1 a promising anticancer therapeutic target. Azenosertib (ZN-c3) is a novel, selective, and orally bioavailable WEE1 inhibitor. The antiproliferative activity of azenosertib on cancer cell lines is consistent with a WEE1-dependent mechanism of action exemplified by reduction of pY15-CDK1 levels and increases in DNA damage markers. Azenosertib further exacerbates the effect of replicative stress and DNA damage by allowing cancer cells to prematurely enter mitosis, leading to mitotic catastrophe and apoptosis. Azenosertib has optimized pharmacokinetic and pharmacodynamic properties, yielding robust tumor growth inhibition in a broad range of tumor models, and is highly effective at delaying the duration of tumor regrowth after cessation of treatment. We have explored various dosing schedules in preclinical efficacy models for azenosertib that preserve antitumor activity with minimal toxicity. Phase I studies with azenosertib as monotherapy have shown preliminary clinical activity in patients with advanced solid tumors. The data presented herein support further studies of azenosertib monotherapy across multiple solid tumor indications.
©2025 The Authors; Published by the American Association for Cancer Research.