Adavosertib (AZD1775): A Comprehensive Monograph on a First-in-Class WEE1 Kinase Inhibitor—From Proof-of-Concept to Clinical Discontinuation

Executive Summary

Adavosertib (AZD1775, MK-1775) is an investigational, orally bioavailable, first-in-class small molecule inhibitor of WEE1 kinase, a critical regulator of the G2/M cell cycle checkpoint. The development of adavosertib was predicated on a compelling scientific rationale centered on the principle of synthetic lethality. In cancer cells with a defective G1/S checkpoint, most commonly due to mutations in the TP53 tumor suppressor gene, the G2/M checkpoint becomes an indispensable mechanism for maintaining genomic integrity. By inhibiting WEE1, adavosertib abrogates this final checkpoint, forcing cells with unrepaired DNA damage into a premature and lethal mitosis, a process termed mitotic catastrophe. This mechanism offered the promise of a therapeutic window, selectively targeting cancer cells while sparing normal tissues with functional G1 checkpoint control.

Originated by Merck & Co. and extensively developed by AstraZeneca, adavosertib was evaluated in a broad and ambitious clinical program spanning numerous solid tumor types. The drug demonstrated consistent and reproducible signals of antitumor activity, both as a monotherapy and in combination with DNA-damaging agents like platinum chemotherapy and PARP inhibitors. The strongest evidence of efficacy emerged in gynecological malignancies, particularly uterine serous carcinoma and ovarian cancer, tumor types characterized by high rates of TP53 mutation and genomic instability. Furthermore, clinical investigation validated the relevance of other biomarkers of replication stress, such as CCNE1 amplification, which correlated with heightened sensitivity to WEE1 inhibition.