Mechanism of action: WEE1 G2 checkpoint kinase inhibitor
AZD1775 is a highly selective, potent, ATP competitive, small molecule inhibitor of WEE1 kinase with an enzyme IC50 of 5.18nM. In vitro, AZD1775 inhibits WEE1 activity and induces DNA damage as well as G2 checkpoint escape in cell based assays with an EC50 of ~80nM. AZD1775 increases cytotoxicity when used in combination with DNA damaging agents, such as gemcitabine, cisplatin, carboplatin and topotecan, in p53-deficient cell lines.
In vivo, AZD1775 is well tolerated and shows enhancement of anti-tumour efficacy by gemcitabine, carboplatin, cisplatin, 5-fluorouracil (5-FU) and capecitabine in nude rat xenograft tumour models. Similarly, in nude mouse xenograft models, AZD1775 treatment results in significant tumour growth inhibition at tolerated doses, and also enhances the anti-tumour growth effect of gemcitabine, carboplatin, and radiation therapy.
Safety and tolerability
AZD1775 is genotoxic, which is considered to be a result of its mechanism of action. No reprotoxicity studies have been conducted to date. In ongoing Phase 1 combination studies, the most common dose limiting adverse events (with chemotherapy) in >10% of patients include: thrombocytopenia, neutropenia, anaemia, diarrhoea, vomiting, nausea, abdominal pain, constipation. Common serious adverse events (with chemotherapy) include: febrile neutropenia, neutropenia, thrombocytopenia [J. Clin. Oncol 31, 2013 (suppl; abstr 5518)].
Preclinical studies of up to 1 month duration have been performed.
Phase 1 studies are investigating target engagement using the phosphorylation status of the pivotal WEE1 substrate, CDC2 (CDK1) in skin as a surrogate for tumour tissue.
Current ongoing trials of AZD1775 include monotherapy and combination therapy with certain DNA damaging agents in solid and ovarian tumours.
Suitable for and exclusions
Preclinical reproductive toxicology data are not available for this compound. The inclusion of women of child-bearing potential using highly effective contraception could be considered based on the risk benefit and in accordance with territory specific requirements.
We would exclude new proposals in areas of overlap with ongoing trials (see link to clinical trials in the Additional Information column to the right). Proposals investigating WEE1 target biology and identifying responsive patient populations with compelling pre-clinical data would be entertained.
Clinical trials for this compound
See all of the clinical trials currently associated with this compound:
Publications for this compound
Find out more about this compound by reading related publications:
Molecular Cancer Therapeutics
Preclinical Evaluation of the WEE1 Inhibitor MK-1775 as Single-Agent Anticancer Therapy
Clinical Cancer Research
MK-1775, a Potent Wee1 Inhibitor, Synergizes with Gemcitabine to Achieve Tumor Regressions, Selectively in p53-Deficient Pancreatic Cancer Xenografts
WEE1 Inhibition by MK-1775 Leads to Tumor Inhibition and Enhances Efficacy of Gemcitabine in Human Sarcomas
Gene information from the NCBi
This compound works on the following genes: