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Immunotherapy in Head and Neck Cancers
Published in R James A England, Eamon Shamil, Rajeev Mathew, Manohar Bance, Pavol Surda, Jemy Jose, Omar Hilmi, Adam J Donne, Scott-Brown's Essential Otorhinolaryngology, 2022
The Wee1 kinase regulates entry into mitosis, by negatively controlling CDK1 and Chk2. AZD-1775 is an agent shown to potentiate DNA-damaging agents in vitro and in vivo, and it is currently undergoing phase I trials.
Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
The WEE 1 tyrosine kinase regulates entry into mitosis by arresting cells with DNA damage at the G2 phase. Since tumor cells lack normal DNA repair mechanisms, they rely heavily on this kinase to serve as a DNA damage checkpoint [93]. In conjunction with cytotoxic agents, inhibition of WEE 1 kinase (via the pyrazolopyrimidine derivative MK-1775) has been adopted for the study of adult solid tumors in Phase I/II trials (NCT01748825, NCT02095132, NCT01357161) [94]. In DAOY and UW228 medulloblastoma cell lines, MK-1775 at nanomolar concentrations inhibited colony formation. Furthermore, in nude mice injected with DAOY cells subcutaneously, oral treatment with MK-1775 led to tumor regression. When tested in conjunction with cisplatin, MK-1775 accelerated apoptosis and inhibited repair of cisplatin-induced DNA damage [92].
Mosquitoes
Published in Gail Miriam Moraru, Jerome Goddard, The Goddard Guide to Arthropods of Medical Importance, Seventh Edition, 2019
Gail Miriam Moraru, Jerome Goddard
Western Equine Encephalitis. Western equine encephalitis (WEE), occurring in the western and central United States, parts of Canada, and parts of South America, has occurred in several large outbreaks (Figure 25.25). There were large epidemics in the northcentral United States in 1941 and in the central valley of California in 1952. The 1941 outbreak involved 3000 cases. From 1964 to 1997, 639 human WEE cases were reported to the U.S. Centers for Disease Control and Prevention (CDC), for a national average of 19 cases per year.65 WEE is generally less severe than EEE and SLE, with a mortality rate of only 2–5%. Cases appear in early to midsummer and are primarily due to bites by infected Culex tarsalis mosquitoes. The incidence of WEE has declined significantly over the past few decades.
Inhibitors of cell cycle checkpoint target Wee1 kinase – a patent review (2003–2022)
Published in Expert Opinion on Therapeutic Patents, 2022
Jingxue Yan, Lili Zhuang, Yong Wang, Yiqing Jiang, Zhenlin Tu, Chao Dong, Yadong Chen, Yong Zhu
According to the biological function of Wee1 protein kinase, it is known to be closely related to cell cycle regulation, and its abnormal expression is related to the development of tumors. In this communication, we present the first comprehensive summary of the structure and some of the bioactivity data of Wee1 inhibitors in patents published since 2003. The chemical structures in all patents involving small-molecule inhibitors of Wee1 can be broadly classified as dianilinopyrimidine derivatives, pyrrolopyrimidine derivatives, pyrrolocarbazole derivatives, pyrimidopyrimidoindazole derivatives, pyrazolopyrimidinone derivatives, and pyridinopyrimidinone derivatives. In terms of chemical structure, the compounds with pyrazolopyrimidinone structure as the parent nucleus exhibited good antitumor activity.
Strategic development of AZD1775, a Wee1 kinase inhibitor, for cancer therapy
Published in Expert Opinion on Investigational Drugs, 2018
Siqing Fu, Yudong Wang, Khandan Keyomarsi, Funda Meric-Bernstein
The activity of Wee1 kinase is highly regulated during the cell cycle. Following its synthesis in the cytoplasm, Wee1 is shuttled into the nucleus by the phosphorylated chaperone protein heat-shock protein 90α (Hsp90α) where it is released from Hsp90α to function on its downstream substrates [23]. In yeast and xenopus, activation of Chk1 kinase by DNA damage phosphorylates the S594 residue of Wee1 protein (equivalent to S642 of human Wee1 protein), which binds to 14-3-3 at interphase but not M phase, leading to even distribution of Wee1 throughout the nuclear interior for its enhanced kinase activity against Cdc2 (equivalent to human Cdk1) [24,25]. In human, activation of AKT kinase by growth factors promotes G2-M cell cycle progression by direct phosphorylation of Wee1 protein on the S642 residue at late S to G2 phase, which binds to 14-3-3θ, resulting in cytoplasmic localization of Wee1 kinase associated with inactivation of Wee1 kinase against Cdk1 [26]. Cdk1 suppression by Wee1 kinase protects the genome integrity through control of replication initiation and nucleotide consumption [27].
Development and implementation of precision therapies targeting base-excision DNA repair in BRCA1-associated tumors
Published in Expert Review of Precision Medicine and Drug Development, 2019
Adel Alblihy, Katia A. Mesquita, Maaz T. Sadiq, Srinivasan Madhusudan
This protein kinase has a vital role in G2/M checkpoint activation via the regulation of cyclin-dependent kinases. However, WEE1 is not directly regulated by DNA damage pathways, but it is essential for physiological progression of the cell cycle [131]. WEE1 is overexpressed in several cancer types such as breast cancer and glioblastoma. Preclinical studies demonstrated that the inhibition of WEE1 by siRNA or WEE1 inhibitors in combination with conventional DNA-damaging agents in cancer cell lines or animal models lead to decrease tumor burden, reduce the viability of cells and improved survival [132].