Alisertib sodium

Alisertib (MLN 8237) sodium is an orally active and selective Aurora A kinase inhibitor (IC50=1.2 nM), which binds to Aurora A kinase resulting in mitotic spindle abnormalities, mitotic accumulation. Alisertib sodium induces apoptosis and autophagy through targeting the AKT/mTOR/AMPK/p38 pathway in leukemic cells. Antitumor activity[1][2][3].

Signaling Pathways >> Epigenetics >> Aurora Kinase

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> Aurora Kinase

Signaling Pathways >> Autophagy >> Autophagy

Aurora A:12.5 nM (IC50)

Aurora B:396.5 nM (IC50)

Alisertib (MLN 8237) leads the MM cells to mitotic spindle abnormalities, mitotic accumulation, as well as inhibition of cell proliferation through apoptosis and senescence. Alisertib up-regulates p53 and tumor suppressor genes p21 and p27[1]. The decreased activity of Alisertib (MLN 8237) for the T217D/W277E Aurora A/TPX2 complex may reflect the increased affinity for ATP induced by cofactor binding to Aurora A[2]. Alisertib (MLN 8237) inhibits cell proliferation with IC50s ranging from 15 to 469 nM in different tumer cell lines[4].

Alisertib (MLN 8237) (30 mg/kg, p.o.) significantly reduces tumor burden and increases overall survival in xenograft-murine model of human-MM[1]. Alisertib (3-30 mg/kg; P.o.; once daily for 3 weeks) causes tumor growth inhibition in solid tumor xenograft models[4]. Animal Model: Nude mice bearing HCT-116 colon tumor xenograft[4] Dosage: 3, 10, or 30 mg/kg Administration: P.o.; once daily for 3 weeks Result: Resulted in a dose-dependent TGI (tumor growth inhibition) of 43.3%, 84.2%, and 94.7% for the 3, 10, and 30 mg/kg groups,respectively.

[1]. Güllü G, et al. A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma Blood June 24, 2010 vol. 115 no. 25 5202-5213.

[2]. Sloane DA, et al. Drug-Resistant Aurora A Mutants for Cellular Target Validation of the Small Molecule Kinase Inhibitors MLN8054 and MLN8237 ACS Chem. Biol., 2010, 5 (6), pp 563-576.

[3]. Bavetsias V, et al. Aurora Kinase Inhibitors: Current Status and Outlook. Front Oncol. 2015 Dec 21;5:278.

[4]. Manfredi MG, et al. Characterization of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays.Clin Cancer Res. 2011 Dec 15;17(24):7614-7624.