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An update on the pharmacokinetics and pharmacodynamics of alisertib, a selective Aurora kinase A inhibitor.
- Source :
-
Clinical and experimental pharmacology & physiology [Clin Exp Pharmacol Physiol] 2016 Jun; Vol. 43 (6), pp. 585-601. - Publication Year :
- 2016
-
Abstract
- Human Aurora kinases, including Aurora kinase A (AURKA), B (AURKB), and C (AURKC), play an essential role in mitotic events such as monitoring of the mitotic checkpoint, creation of bipolar mitotic spindle and alignment of centrosomes on it, also regulating centrosome separation, bio-orientation of chromosomes and cytokinesis. AURKA and AURKB are key regulators of mitosis and centrosome via polymerizing microfilaments and controlling chromatid segregation. In particular, AURKA plays critical roles in the regulation of mitotic entry, centrosome function, bipolar spindle assembly, and chromosome segregation. AURKA has been found to be overexpressed in various solid and haematological cancers and has been linked with poor prognosis. Its important role in cancer initiation, growth, and metastasis has brought the focus to search for potent and selective AURKA inhibitors for cancer treatment. MLN8237, also known as alisertib, is one selective AURKA inhibitor that has shown remarkable anticancer effects in preclinical studies. Alisertib exhibits favourable pharmacokinetic properties. Alisertib has generally showed good partial response rates of 4-52% and good safety profiles in Phase I and II trials when it is solely administered as well as combined with cytotoxic chemotherapeutic drugs. Recently, the multicentre, randomized Phase III study of alisertib in patients with relapsed or refractory peripheral T-cell lymphoma has been discontinued due to unsatisfactory efficacy. The low risk of side effects, accessibility, and effectiveness of alisertib makes it a new promising anticancer therapy and further mechanistic and clinical studies are warranted.<br /> (© 2016 John Wiley & Sons Australia, Ltd.)
- Subjects :
- Animals
Antineoplastic Agents therapeutic use
Aurora Kinase A chemistry
Binding Sites physiology
Clinical Trials as Topic methods
Humans
Neoplasms drug therapy
Neoplasms enzymology
Protein Kinase Inhibitors therapeutic use
Protein Structure, Secondary
Antineoplastic Agents pharmacokinetics
Aurora Kinase A antagonists & inhibitors
Aurora Kinase A metabolism
Protein Kinase Inhibitors pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1440-1681
- Volume :
- 43
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Clinical and experimental pharmacology & physiology
- Publication Type :
- Academic Journal
- Accession number :
- 26999067
- Full Text :
- https://doi.org/10.1111/1440-1681.12571