1028486-01-2 Usage
Description
MLN-8237, also known as Alisertib, is a selective Aurora A inhibitor with high potency and selectivity, characterized by an IC50 of 1.2 nM in a cell-free assay and more than 200-fold higher selectivity for Aurora A than Aurora B. It is an off-white solid that disrupts the Aurora A-Myc complex, leading to Myc degradation in Myc amplified neuroblastomas and p53-mutant human hepatocellular carcinoma cells. Additionally, it induces apoptosis and autophagy in breast cancer and melanoma cells via suppression of the p38 MAPK pathway activation.
Uses
Used in Oncology:
MLN-8237 is used as an anticancer agent for the treatment of patients with advanced solid tumors. It targets Aurora A, a key regulator of cell division, and has been found to induce apoptosis and autophagy in various cancer types, including breast cancer and melanoma.
Used in Drug Development:
MLN-8237 is used as a research tool in the development of new cancer therapies. Its high selectivity and potency make it a valuable compound for studying the role of Aurora A in cancer progression and for identifying potential synergistic effects with other drugs.
Used in Preclinical and Clinical Research:
MLN-8237 is used in preclinical and clinical research to evaluate its safety, efficacy, and potential side effects in treating various types of cancer. It has reached Phase 3 in clinical trials, indicating its potential as a viable treatment option for cancer patients.
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.
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
Check Digit Verification of cas no
The CAS Registry Mumber 1028486-01-2 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,0,2,8,4,8 and 6 respectively; the second part has 2 digits, 0 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 1028486-01:
(9*1)+(8*0)+(7*2)+(6*8)+(5*4)+(4*8)+(3*6)+(2*0)+(1*1)=142
142 % 10 = 2
So 1028486-01-2 is a valid CAS Registry Number.
InChI:InChI=1S/C27H20ClFN4O4/c1-36-21-5-3-4-20(29)23(21)25-19-10-15(28)6-8-17(19)24-14(12-30-25)13-31-27(33-24)32-16-7-9-18(26(34)35)22(11-16)37-2/h3-11,13H,12H2,1-2H3,(H,34,35)(H,31,32,33)
1028486-01-2Relevant articles and documents
Small molecule with Aurora kinase degradation activity, preparation method and application thereof
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, (2020/12/30)
The invention discloses a small molecule with Aurora kinase degradation activity, a preparation method and application thereof. According to the invention, 12 Aurora-A protein degradation agents basedon a PROTAC technology are obtained by using three E3 u
COMPOUNDS FOR INHIBITING MITOTIC PROGRESSION
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Page/Page column 29-30, (2008/12/05)
The present invention relates to compounds of formula (I) : and methods for the treatment of cancer. In particular, the invention provides potent inhibitors of Aurora A kinase, pharmaceutical compositions comprising the compounds, and methods of using the compounds for the treatment of cancer.
