Wee1

Wee1

Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe. It influences cell size by inhibiting the entry into mitosis, through inhibiting Cdk1. It has homologues in many other organisms, including mammals. Wee1 inhibits Cdk1 by phosphorylating it on two different sites, Tyr15 and Thr14.

An overview of WEE1

Nurse et al. isolated WEE1 protein kinase from the fission yeast cell (S. pombe) in 1975, which belongs to the silk/threonine protein kinase family. Because it can inhibit cell mitosis by inhibiting the activity of CDC2, thereby controlling the cell cycle clock. As a result, it is called the "WEE" family. The WEE1 kinase family is highly conserved in evolution, and a homologous gene encoding product of WEE1 has also been found in humans. Studies have shown that WEE1 has an important role in maintaining cancer cell survival. Moreover, WEE1 is indispensable for embryonic development, neuronal polarization, osteogenic differentiation, gastrointestinal circadian clock, plant differentiation and root phenotype, and cell size. At present, anti-cancer research with WEE1 as a therapeutic target has become a hot topic in current research.

Inhibition of WEE1

WEE1-specific small molecule inhibitors such as MK-1775 have entered clinical trials and are used in tumors with high expression of WEE1. MK-1775 can enhance DNA damage in human lung cancer, breast cancer, skin cancer, and prostate cancer cells. WEE1 inhibitors can induce cytotoxicity in combination with Chk1 inhibitors. WEE1 inhibitors are well tolerated with fewer adverse reactions. MK-1775 has a high affinity for WEE1 and is the preferred WEE1 inhibitor. In cancer cells recurring after chemotherapy for medulloblastoma, vulvar squamous cell carcinoma, and malignant ovarian cancer, a single WEE1 inhibitor, AZD1775, can inhibit tumors. In the absence of histone H3K36 cancer cells, synthetic lethal effects are very sensitive to WEE1 inhibition. Inhibition of WEE1 alone leads to S phase arrest and increased apoptosis. The WEE1 inhibitor AZD1775 and the Chk1 inhibitor PD00477736 have a strong synergistic effect on sheath cell lymphoma cells.

WEE1 and diseases

Wee1 protein kinase plays an important role in the S phase and G2/M transition phase of the cell cycle. In the event of cellular DNA damage, the cell cycle can be arrested for repair of damaged DNA. In many tumors, Wee1 protein kinase is overexpressed, and inhibition or down-regulation of Wee1 protein kinase can cause mitotic catastrophe, leading to apoptosis. Therefore, Wee1 protein kinase may be an ideal target for tumor therapy.

References:

Harris, P. S., Venkataraman, S., Alimova, I., Birks, D. K., Balakrishnan, I., & Cristiano, B., et al. (2014). Integrated genomic analysis identifies the mitotic checkpoint kinase wee1 as a novel therapeutic target in medulloblastoma. Molecular Cancer,13,1(2014-03-24), 13(1), 72-72.

Jjj, G., & Jhm, S. (2017). Molecular pathways: targeting the protein kinase wee1 in cancer. Clinical Cancer Research An Official Journal of the American Association for Cancer Research, 23(16), clincanres.0520.2017.

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