Clinical cancer research, 2017-08, Vol.23 (16), p.4540-4544
2017
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Details
- Autor(en) / Beteiligte
- Titel
- Molecular Pathways: Targeting the Protein Kinase Wee1 in Cancer
- Ist Teil von
- Clinical cancer research, 2017-08, Vol.23 (16), p.4540-4544
- Ort / Verlag
- United States: American Association for Cancer Research Inc
- Erscheinungsjahr
- 2017
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Wee1 is a protein kinase that regulates the G checkpoint and prevents entry into mitosis in response to DNA damage. Cyclin-dependent kinases (CDK) are a family of 14 serine/threonine protein kinases that coordinate the progression through the cell cycle. The Cdc2/cyclin B complex controls the progression from G into mitosis. There are two mechanisms by which the G checkpoint is initiated in response to DNA damage: phosphorylation of Cdc25c by CHK1 and of the Wee1 kinase, which phosphorylates Cdc2. Blockade at the G checkpoint is especially important for p53-mutant cells because these tumors mainly rely on DNA repair at the G checkpoint. AZD1775 (formerly MK-1775) is a small-molecule, pyrazol-pyrimidine derivative and potent and ATP-competitive specific inhibitor of the Wee1 kinase. Several preclinical and clinical studies demonstrated encouraging antitumor effects with manageable side effects of the combination of Wee1 inhibition and DNA-damaging agents. Promising combination schedules are being investigated at the moment, for example, combining PARP inhibition and Wee1 inhibition. Also, a weekly schedule with carboplatin and AZD1775 warrants investigation aimed at further improving the antitumor effect. .
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1078-0432eISSN: 1557-3265DOI: 10.1158/1078-0432.ccr-17-0520Titel-ID: cdi_proquest_miscellaneous_1892331706
- Format
- –
- Schlagworte
- Animals, Anticancer properties, Antineoplastic Combined Chemotherapy Protocols - adverse effects, Antineoplastic Combined Chemotherapy Protocols - therapeutic use, Antitumor activity, Cancer, Carboplatin, Carboplatin - administration & dosage, Carboplatin - adverse effects, Cdc2 protein, CDC2 Protein Kinase - metabolism, Cell cycle, Cell Cycle Proteins - antagonists & inhibitors, Cell Cycle Proteins - metabolism, CHK1 protein, Clinical Trials as Topic, Cyclin B, Cyclin-dependent kinases, Damage prevention, Deoxyribonucleic acid, DNA, DNA damage, DNA repair, Drug Screening Assays, Antitumor, Enzyme inhibitors, G2 Phase Cell Cycle Checkpoints - drug effects, Humans, Inhibition, Kinases, Mitosis, Models, Biological, Neoplasms - drug therapy, Neoplasms - metabolism, Nuclear Proteins - antagonists & inhibitors, Nuclear Proteins - metabolism, p53 Protein, Phosphorylation, Phosphorylation - drug effects, Poly(ADP-ribose) polymerase, Protein kinase, Protein-Tyrosine Kinases - antagonists & inhibitors, Protein-Tyrosine Kinases - metabolism, Proteins, Pyrazoles - administration & dosage, Pyrazoles - adverse effects, Pyrimidines - administration & dosage, Pyrimidines - adverse effects, Schedules, Serine, Side effects, Signal Transduction - drug effects, Threonine, Tumors