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Review
. 2013 Oct 1;12(19):3159-64.
doi: 10.4161/cc.26062. Epub 2013 Aug 26.

Wee1 kinase as a target for cancer therapy

Khanh Do  1 , James H Doroshow, Shivaani Kummar
Affiliations
Review

Wee1 kinase as a target for cancer therapy

Khanh Do et al. Cell Cycle. .

Abstract

Wee1, a protein kinase, regulates the G 2 checkpoint in response to DNA damage. Preclinical studies have elucidated the role of wee1 in DNA damage repair and the stabilization of replication forks, supporting the validity of wee1 inhibition as a viable therapeutic target in cancer. MK-1775, a selective and potent small-molecule inhibitor of wee1, is under clinical development as a potentiator of DNA damage caused by cytotoxic chemotherapies. We present a review of the role of wee1 in the cell cycle and DNA replication and summarize the clinical development to date of this novel class of anticancer agents.

Keywords: DNA damage; G2 checkpoint; MK 1775; cell cycle; cyclin-dependent kinase.

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Figures

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Figure 1. Cyclin-dependent kinase regulation of the cell cycle. Cell cycle checkpoints serve to halt progression of the cell cycle in response to DNA damage, allowing time for DNA repair and the maintenance of genomic integrity. Cyclin-dependent kinases regulate the progression through cell cycle checkpoints. Abbreviations: Cdk, cyclin-dependent kinase.
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Figure 2. DNA damage detected at the G2 checkpoint. Depending on the type of genotoxic stress, either ataxia-telangectasia mutated (ATM) protein kinase or ataxia-telangiectasia-related (ATR) protein kinase are preferentially activated. ATR is the main kinase responsible for the phosphorylation and activation of checkpoint kinase 1 (Chk1). Chk1, in turn, concomitantly phosphorylates wee1 and Cdc25C, thereby activating wee1 kinase activity and inactivating Cdc25C phosphatase activity. Wee1 phosphorylates and inactivates Cdk1/Cdc2-bound cyclin B on its tyrosine15 residue, resulting in cell cycle arrest at G2, allowing time for DNA repair. Abbreviations: ATM, ataxia-telangectasia mutated protein kinase; ATR, ataxia-telangiectasia-related protein kinase; Chk, checkpoint kinase; Cdk, cyclin-dependent kinase; Cdc, cell division cycle phosphatase.
See this image and copyright information in PMC

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