AZD1775

AZD1775, also known as adavosertib, is a selective small-molecule inhibitor of the protein kinase WEE1. WEE1 regulates the G2/M cell cycle checkpoint by phosphorylating and inhibiting CDK1, preventing cells from entering mitosis in the presence of DNA damage. Inhibiting WEE1 abrogates this checkpoint, pushing cells with DNA damage into mitosis and increasing the likelihood of mitotic catastrophe and cell death. The strategy is particularly aimed at tumors with defective p53, which lack a robust G1/S checkpoint and thus rely more on the G2/M arrest for DNA damage repair.

Development and clinical research: AZD1775 was developed by AstraZeneca and has been studied in multiple phase I and II trials across various solid tumors. It has been evaluated in combination with DNA-damaging therapies, including platinum-based chemotherapy and radiotherapy, as well as with other agents, in cancers such as ovarian, pancreatic, and head and neck cancers. Some early trials reported responses or disease stabilization in patients whose tumors harbored p53 mutations, but results have varied. The safety profile commonly includes hematologic toxicities, particularly neutropenia and thrombocytopenia, along with fatigue and gastrointestinal effects; these adverse events have influenced dose selection and schedule in different studies.

Regulatory status: AZD1775 has not received regulatory approval and remains investigational. Ongoing trials seek to define optimal patient selection, dosing, and combination regimens to determine its potential clinical benefit.