Biologically Targeted Agents in Head and Neck Cancers
John C Watkinson, Raymond W Clarke, Terry M Jones, Vinidh Paleri, Nicholas White, Tim Woolford in Head & Neck Surgery Plastic Surgery, 2018
The Wee1 kinase regulates entry into mitosis, by negatively controlling CDK1 and 2. In a similar fashion to ATR and Chk1, it is active during normal unperturbed cell division, playing a role in the maintenance of genome integrity. A Wee1 kinase inhibitor (AZD-1775, formerly MK-1775) has been shown to sensitize p53-deficient tumour cell lines to radiation, with abrogation of radiation-induced G2 arrest and premature entry into mitosis.89 The drug has also been shown to potentiate DNA-damaging agents in vitro and in vivo,90, 91 and has reached a number of phase I trials. Cdc25 phosphatase is another G2 checkpoint target92 and inhibitors have been developed that have shown activity against tumour cells and xenografts.93
Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Surinder K. Batra, Moorthy P. Ponnusamy in Gene Regulation and Therapeutics for Cancer, 2021
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].
Immunotherapy in Head and Neck Cancers
R James A England, Eamon Shamil, Rajeev Mathew, Manohar Bance, Pavol Surda, Jemy Jose, Omar Hilmi, Adam J Donne in 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.
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].
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.
Prexasertib: an investigational checkpoint kinase inhibitor for the treatment of high-grade serous ovarian cancer
Published in Expert Opinion on Investigational Drugs, 2020
Giulio Evangelisti, Fabio Barra, Melita Moioli, Paolo Sala, Sara Stigliani, Claudio Gustavino, Sergio Costantini, Simone Ferrero
The degradation of CDC25A and cytosolic sequestration of CDC25B-C prevents the activation of CDK1 and CDK2; this usually leads to the stops of the cell cycle for fixing DNA defects or activating the programmed cell death at G1 and G2 checkpoints [4547–48]. The WEE1 kinase contributes to regulating the activation of CDK1 negatively, thus determining the arrest of progression of the cell cycle at G2-M checkpoint, allowing to repair DNA defects [49]. Inhibition of WEE1 demonstrated to increases replication origin firing and double-stranded breaks accumulation, subsequently promoting premature entry into mitosis and mitotic catastrophe [5051–52]. AZD1775 (MK-1775) is the only WEE1 inhibitor tested as monotherapy and in combination with conventional CT for the treatment of HGSOC [53,54]. This drug showed encouraging antitumor activity in combination with carboplatin in the treatment of platinum-refractory or platinum-resistant HGSOC; moreover, it proved to be effective in treating HGSOC with TP53 mutation or with the defective function of DNA damage repairing system due to BRCA1-2 mutation [53,54].
Related Knowledge Centers
- Homology
- Protein Kinase
- Cell Cycle
- Mitosis
- Serine/Threonine-Specific Protein Kinase
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- Cyclin-Dependent Kinase 1
- Kinase
- Ultrasensitivity
- Pom1