An update on the pharmacokinetics and pharmacodynamics of alisertib, a selective Aurora kinase A inhibitor

Abstract

SUMMARYHuman 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, bioorientation 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.

Crizotinib induces apoptosis and gene expression changes in ALK+ anaplastic large cell lymphoma cell lines; brentuximab synergizes and doxorubicin antagonizes

“…We investigated the effects of an Aurora kinase A inhibitor, alisertib, and found no significant effects on gene expression at the dosage utilized. It, like BV and vinblastine, functions primarily at the level of mitosis but also has proposed effects on gene expression involving JAK/STAT, PI3K, NFkβ, and related pathways . Our results suggest that such effects may not occur in vitro at doses adequate for mitotic death.…”

Aurora A kinase inhibition enhances oncolytic herpes virotherapy through cytotoxic synergy and innate cellular immune modulation

“…Additionally, alisertib is an effective clinical therapeutic shown to induce stable disease and partial responses in phase I and II studies [24, 25]. Alisertib is of particular interest for neuroblastoma due to preclinical efficacy in xenograft models [21] and the discovery that Aurora A Kinase stabilizes the oncogene MYCN [26, 27].…”

Insights into the non-mitotic functions of Aurora kinase A: more than just cell division

“…Alisertib (MLN82374, Millennium pharmaceuticals) is the AURKA inhibitor most extensively studied and tested in clinical trials [127]. It has a 200-fold better selectivity for AURKA than for AURKB, with an in vitro IC50 of 1.2 nM and negligible off-target effects towards the majority of structurally-related kinases [128].…”

“…Interestingly, it was shown to potentiate the effect of specific therapeutic options for Chronic Myeloid Leukaemia as Nilotinib, thanks to the capacity of Alisertib to inhibit BCR-Abl and its T315I mutated form [129]. Alisertib was tested in clinical trials (Phase I/II) for several cancers, including lymphomas, leukaemia, gastric, ovarian and breast cancers [127]. Both alone or in combination with other drugs, Alisertib generally abolishes cell proliferation by inducing a cell cycle arrest, mitotic abnormalities and cell death [130].…”