Description
Alisertib (MLN8237) is a selective Aurora A inhibitor with IC50 of 1.2 nM in a cell-free assay. It has >200-fold higher selectivity for Aurora A than Aurora B. Phase 3.
In vitro
MLN8237 shows >200-fold higher selectivity for Aurora A than the structurally related Aurora B with an IC50 of 396.5 nM, and does not have any significant activity against 205 other kinases. [1] MLN8237 (0.5 μM) treatment inhibits the phosphorylation of Aurora A in MM1.S and OPM1 cells, without affecting the Aurora B mediated histone H3 phosphorylation. MLN8237 significantly inhibits cell proliferation in multiple myeloma (MM) cell lines with IC50 values of 0.003-1.71 μM. MLN8237 displays more potent anti-proliferation activity against primary MM cells and MM cell lines in the presence of BM stroma cells, as well as IL-6 and IGF-1 than against MM cells alone. MLN8237 (0.5 μM) induces 2- to 6-fold increase in G2/M phase in primary MM cells and cell lines, as well as significant apoptosis and senescence, involving the up-regulation of p53, p21 and p27, as well as PARP, caspase 3, and caspase 9 cleavage. In addition, MLN8237 shows strong synergistic anti-MM effect with dexamethasone, as well as additive effect with doxorubicin and bortezomib.MLN8237 (0.5 μM) treatment causes the inhibition of colony formation of FLO-1, OE19, and OE33 esophageal adenocarinoma cell lines, and induces a significant increase in the percentage of polyploid cells, and subsequently an increase in the percentage of cells in the sub-G1 phase, which can be further enhanced in combination with cisplatin (2.5 μM), involving the higher induction of TAp73β, PUMA, NOXA, cleaved caspase-3, and cleaved PARP as compared with a single-agent treatment.
In vivo
MLN8237 significantly reduces the tumor burden with tumor growth inhibition (TGI) of 42% and 80% at 15 mg/kg and 30 mg/kg, respectively, and prolongs the survival of mice compared with the control.
Description
Alisertib (MLN8237, 1028486-01-2) is a highly selective and potent (IC50?= 1 nM) cell permeable inhibitor of Aurora A with off-target binding at GABAA?(IC50?= 490 nM).1?It disrupts the Aurora A-Myc complex leading to Myc degradation2?in Myc amplified neuroblastomas3?and p53-mutant human hepatocellular carcinoma cell4. Alisertib has been found to induce apoptosis and autophagy in breast cancer5?and melanoma6?cells?via?suppression of activation of the p38 MAPK pathway.
Chemical Properties
Off-White Solid
Uses
An Aurora kinase inhibitor, used to treat patients with advanced solid tumors.
Definition
ChEBI: 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid is a benzazepine.
References
1) Sells?et al.?(2015),?MLN8054 and Alisertib (MLN8237):Discovery of Selective Oral Aurora A Inhibitors; ACS Med. Chem. Lett.?6?630
2) Richards?et al.?(2016),?Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors; Proc. Natl. Acad. Sci. USA?113?13726
3) Brockmann?et al.?(2013),?Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma; Cancer Cell?24?75
4) Dauch?et al.?(2016),?A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer; Nat. Med.?22?744
5) Li?et al.?(2015),?The investigational Aurora kinase A inhibitor alisertib (MLN8237) induces cell cycle G2/M arrest, apoptosis, and autophagy via p38 MAPK and Akt/mTOR signaling pathways in human breast cancer cells; Drug Des. Devel. Ther.?16?1627
6) Shang?et al.?(2017),?Alisertib promotes apoptosis and autophagy in melanoma through p38 MAPK-mediated aurora a signaling; Oncotarget?8?107076
