MLN82379 (Alisertib) is a second-generation, orally bioavailable, highly selective small molecule inhibitor of the serine/threonine protein kinase Aurora A kinase with potential antineoplastic activity. MLN8237 (Alisertib) binds to and inhibits Aurora A kinase, which may result in disruption of the assembly of the mitotic spindle apparatus, disruption of chromosome segregation, and inhibition of cell proliferation.
|Cell lines||HCT-116, SW480, DLD-1, H460, MDA-MB-231, PC3, SKOV3 cell lines|
|Preparation method||BrdU in vitro cell proliferation assay Thirteen tumor cell lines treated with increasing concentrations of alisertib over 96 hours were subjected to 5-bromo-2-deoxyuridine (BrdU) incorporation as a measurement of cellular proliferation. Proliferation of each cell line was measured using the cell proliferation ELISA, BrdU colorimetric kit according to the manufacturer's recommendations (Roche).|
|Animal models||Mice bearing the disseminated, CD20-positive, non-Hodgkin's lymphoma model OCI-LY19|
|Formulation||10% 2-hydroxypropyl-β-cyclodextrin and 1% sodium bicarbonate|
|Dosages||20 mg/kg twice daily or 30 mg/kg once daily|
|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.
|Chemical Name||Benzoic acid, 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d]benzazepin-2-yl]amino]-2-methoxy-|
|Source||Journal of Hematology & Oncology (2017). Figure 7. MLN8237 (Abmole Bioscience)|
|Cell Lines||U251, U87 and U118 cell lines|
|Incubation Time||48 h|
|Results||Treatment with two other aurora kinase inhibitors, AZD1152 and MLN8237, demonstrated similar results (Fig. 7d).|
J Hematol Oncol 2017 Jun 8;10(1):115.
SIX3, a tumor suppressor, inhibits astrocytoma tumorigenesis by transcriptional repression of AURKA/B.
MLN8237 purchased from AbMole
Pediatric Phase 1 Trial and Pharmacokinetic Study of MLN8237, an Investigational Oral Selective Small Molecule Inhibitor of Aurora Kinase A: A Children's Oncology Group Phase 1 Consortium study.
Mosse YP et al. Clin Cancer Res. 2012 Sep 17. PMID: 22988055.
Phase II study of MLN8237 (alisertib), an investigational Aurora A kinase inhibitor, in patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.
Matulonis UA et al. Gynecol Oncol. 2012 Oct;127(1):63-9. PMID: 22772063.
Phase I Study of Aurora A Kinase Inhibitor MLN8237 in Advanced Solid Tumors: Safety, Pharmacokinetics, Pharmacodynamics, and Bioavailability of Two Oral Formulations.
Dees EC et al. Clin Cancer Res. 2012 Sep 11;18(17):4775-84. PMID: 22767670.
Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors.
Cervantes A et al. Clin Cancer Res. 2012 Sep 1;18(17):4764-74. PMID: 22753585.
Additive effects of vorinostat and MLN8237 in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines.
Muscal JA et al. Invest New Drugs. 2012 Jun 6. PMID: 22669335.
|Related Aurora Kinase Products|
SNS-314 is a potent and selective inhibitor of Aurora A, Aurora B and Aurora C with IC50 of 9 nM, 31 nM, and 3 nM, respectively.
GSK1070916 is a reversible and ATP-competitive inhibitor of Aurora B/C with IC50 of 3.5 nM/6.5 nM. It displays >100-fold selectivity against the closely related Aurora A-TPX2 complex.
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.
MK-5108 (VX-689) is a highly selective Aurora A inhibitor with IC50 of 0.064 nM and is 220- and 190-fold more selective for Aurora A than Aurora B/C, while it inhibits TrkA with less than 100-fold selectivity.
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.