MLN8054 is an orally bioavailable, highly selective small molecule inhibitor of Aurora with IC50s of 0.004uM and 0.172uM. for Aurora A and Aurora B.Auora kinase inhibitor MLN8054 binds to and inhibits Aurora kinase A, resulting in disruption of the assembly of the mitotic spindle apparatus, disruption of chromosome segregration, and inhibition of cell proliferation.
|Cell lines||HCT116, PC-3, SW480, DLD-1, MCF-7, MDA-MB-231, Calu-6, H460 and SKOV-3 cell lines|
|Preparation method||Cell Viability Analysis. Human tumor cell lines obtained from the American Type Culture Collection were grown in 96-well cell culture dishes according to the distributor's recommendations. MLN8054, diluted in DMSO, was added to the cells in 2-fold serial dilutions to achieve final concentrations ranging from 10 to 0.04 mM. MLN8054 at each dilution was added in triplicate with each replicate on a separate plate. Cells treated with DMSO (n = 6 wells per plate; 0.2% final concentration) served as the untreated control. The cells were treated with MLN8054 for 96 h at 37°C in a humidified cell culture chamber. Cell viability in each cell line was measured by using the Cell Proliferation ELISA, BrdU colorimetric kit according to the manufacturer's recommendations (Roche).|
|Incubation time||96 hr|
|Animal models||Female (HCT-116) and male (PC3) athymic nude NCR (nu/nu) mice|
|Formulation||10% hydroxypropyl-β-cyclodextrin (Sigma) with 5% sodium bicarbonate|
|Dosages||10 or 30 mg/kg BID or 30mg/kg QD for 21 consecutive days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Source||Int J Radiat Oncol Biol Phys (2011). Figure 1. MLN8054|
|Cell Lines||DU145 cells|
|Incubation Time||1 h|
|Results||When MLN8054 was administered in combination with radiation, total Aurora-A remained elevated, but phospho-Aurora-A levels were reduced nearly to baseline levels, indicating abrogation of Aurora-A activity|
Molecular dynamics and free energy studies on Aurora kinase A and its mutant bound with MLN8054: insight into molecular mechanism of subtype selectivity.
Yang Y et al. Mol Biosyst. 2012 Sep 18. PMID: 22990663.
Combined inhibition of cellular pathways as a future therapeutic option in fatal anaplastic thyroid cancer.
Wunderlich A et al. Endocrine. 2012 Apr 5. PMID: 22477151.
MLN8054, a small molecule inhibitor of aurora kinase a, sensitizes androgen-resistant prostate cancer to radiation.
Moretti L et al. Int J Radiat Oncol Biol Phys. 2011 Jul 15;80(4):1189-97. PMID: 21514073.
Phase I assessment of new mechanism-based pharmacodynamic biomarkers for MLN8054, a small-molecule inhibitor of Aurora A kinase.
Chakravarty A et al. Cancer Res. 2011 Feb 1;71(3):675-85. PMID: 21148750.
Phase I study of the selective Aurora A kinase inhibitor MLN8054 in patients with advanced solid tumors: safety, pharmacokinetics, and pharmacodynamics.
Macarulla T et al. Mol Cancer Ther. 2010 Oct;9(10):2844-52. PMID: 20724522.
Drug-resistant aurora A mutants for cellular target validation of the small molecule kinase inhibitors MLN8054 and MLN8237.
Sloane DA et al. ACS Chem Biol. 2010 Jun 18;5(6):563-76. PMID: 20426425.
MLN8054, an inhibitor of Aurora A kinase, induces senescence in human tumor cells both in vitro and in vivo.
Huck JJ et al. Mol Cancer Res. 2010 Mar;8(3):373-84. PMID: 20197380.
Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase.
Manfredi MG, et al. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4106-11. PMID: 17360485.
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PHA-680632 is potent inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 27 nM, 135 nM and 120 nM, respectively. It has 10- to 200-fold higher IC50 for FGFR1, FLT3, LCK, PLK1, STLK2, and VEGFR2/3.
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PF-03814735 is a novel, potent and reversible inhibitor of Aurora A/B with IC50of 0.8 nM/5 nM, is less potent to Flt3, FAK, TrkA, and minimally active to Met and FGFR1.
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