title: An update on the pharmacokinetics and pharmacodynamics of alisertib, a selective Aurora kinase A inhibitor.
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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors.forename: Cameron T
authors.initials: CT
authors.lastname: Durlacher
authors.affiliation: Department of Pharmacy, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhi-Ling
authors.initials: ZL
authors.lastname: Li
authors.affiliation: Department of General Surgery, The First People's Hospital of Shunde Affiliated to Southern Medical University, Shunde, Foshan, Guangdong.
authors.forename: Xiao-Wu
authors.initials: XW
authors.lastname: Chen
authors.affiliation: Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre & Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China.
authors.forename: Zhi-Xu
authors.initials: ZX
authors.lastname: He
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D002986:Clinical Trials as Topic / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017433:Protein Structure, Secondary
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D064096:Aurora Kinase A
keywords: Aurora kinase A; Aurora kinase inhibitor; alisertib; apoptosis; autophagy; cancer therapy