adavosertib

Adavosertib, also known as AZD1775, is a selective small-molecule inhibitor of the WEE1 kinase. It was developed to disrupt the G2/M cell cycle checkpoint by inhibiting WEE1’s phosphorylation of CDK1 and CDK2, thereby forcing cells with DNA damage to enter mitosis. In tumor cells, this can enhance the cytotoxic effects of DNA-damaging therapies and promote mitotic catastrophe.

Rationale for use centers on the reliance of many cancer cells on the G2/M checkpoint, particularly when p53 function is compromised. By blocking WEE1, adavosertib aims to abrogate the G2/M arrest, increase replication stress, and sensitize cancer cells to chemotherapy, radiotherapy, and other DNA-damaging treatments. This mechanism is intended to preferentially affect tumor cells while sparing normal cells with intact checkpoints, though toxicities are an important consideration.

Clinical development has explored adavosertib in multiple solid tumors, especially in combination with platinum-based chemotherapy (such as cisplatin or carboplatin), gemcitabine, radiation therapy, and, in some studies, PARP inhibitors. Trials have spanned ovarian, pancreatic, cervical, head and neck cancers, among others, with various regimens and schedules. While some trials have reported anti-tumor activity and potential synergistic effects, the broader development has been limited by safety concerns and the lack of regulatory approval to date.

Safety and tolerability are central to adavosertib’s assessment. The most common and dose-limiting toxicities observed in trials are hematologic, including thrombocytopenia, anemia, and neutropenia, along with fatigue, nausea, and diarrhea. Ongoing research continues to optimize dosing, identify predictive biomarkers, and refine combination strategies to balance efficacy with tolerability.