TY - JOUR
T1 - Strategic development of AZD1775, a Wee1 kinase inhibitor, for cancer therapy
AU - Fu, Siqing
AU - Wang, Yudong
AU - Keyomarsi, Khandan
AU - Meric-Bernstein, Funda
N1 - Funding Information:
One of the reviewers has received research funding from AZ and served as an advisor. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.
PY - 2018/9/2
Y1 - 2018/9/2
N2 - Introduction: Wee1 kinase controls the G2-M checkpoint. Wee1 inhibition by AZD1775 allows cells with a deregulated G1 checkpoint to progress, resulting in catastrophe and apoptosis. The challenges ahead are in the establishment of the optimum dosing schedule either alone or in combination and the identification of patients with specific biomarker profiles who benefit most. Areas covered: This article provides an overview of AZD1775, based on English peer-reviewed articles on MEDLINE. The authors highlight the data from the published preclinical and clinical studies. Expert opinion: A majority of the current clinical trials focus on AZD1775 combined with chemotherapy or radiation. Treatment with AZD1775 was tolerated, and antitumor activity has been observed, especially in patients with advanced malignancies harboring G1 checkpoint aberrations and/or DNA damage repair defects. Thus, identification of the molecular subtypes that benefit most from the treatment with AZD1775 alone or in combination may provide a novel strategy for cancer therapy. Research is needed for devising regimens to explore AZD1775 in combination with biologically targeted agents and/or immunotherapy (low dose vs. high dose, intermittent vs. continuous, sequential vs. concurrent, etc.) for identifying potential biomarkers predictive of response and survival.
AB - Introduction: Wee1 kinase controls the G2-M checkpoint. Wee1 inhibition by AZD1775 allows cells with a deregulated G1 checkpoint to progress, resulting in catastrophe and apoptosis. The challenges ahead are in the establishment of the optimum dosing schedule either alone or in combination and the identification of patients with specific biomarker profiles who benefit most. Areas covered: This article provides an overview of AZD1775, based on English peer-reviewed articles on MEDLINE. The authors highlight the data from the published preclinical and clinical studies. Expert opinion: A majority of the current clinical trials focus on AZD1775 combined with chemotherapy or radiation. Treatment with AZD1775 was tolerated, and antitumor activity has been observed, especially in patients with advanced malignancies harboring G1 checkpoint aberrations and/or DNA damage repair defects. Thus, identification of the molecular subtypes that benefit most from the treatment with AZD1775 alone or in combination may provide a novel strategy for cancer therapy. Research is needed for devising regimens to explore AZD1775 in combination with biologically targeted agents and/or immunotherapy (low dose vs. high dose, intermittent vs. continuous, sequential vs. concurrent, etc.) for identifying potential biomarkers predictive of response and survival.
KW - AZD1775
KW - DNA damage repair
KW - Wee1 kinase
KW - and early drug development
KW - cell cycle checkpoints
KW - immunotherapy
KW - targeted therapy
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U2 - 10.1080/13543784.2018.1511700
DO - 10.1080/13543784.2018.1511700
M3 - Review article
C2 - 30102076
AN - SCOPUS:85052854986
SN - 1354-3784
VL - 27
SP - 741
EP - 751
JO - Expert Opinion on Investigational Drugs
JF - Expert Opinion on Investigational Drugs
IS - 9
ER -