A4110-5mg | MLN8237 (Alisertib) [1028486-01-2] Clinisciences

Background

The orally bioavailable agent, MLN8237 (also known as alisertib), is a potent small-molecule inhibitor of Aurora A kinase (AAK) which is overexpressed in several types of tumor and associated with oncogenesis and tumor progression. It was developed from its predecessor, MLN8054, in order to minimize the benzodiazepine-like effects seen with MLN8054. The inhibitory effect of MLN8237 is ATP-competitive, reversible and AAK-specific with an inhibition constant (K_i) of 0.43 nmol/L. MLN8237 is being investigated to treat advanced malignancies, due to its both in vitro and in vivo activities against a broad range of tumor types.

Reference

E. Claire Dees, Roger B. Cohen, Margaret von Mehren, Thomas E. Stinchcombe, Hua Liu, Karthik Venkatakrishnan, Mark Manfredi, Howard Fingert, Howard A. Burris III, and Jeffrey R. Infante. Phase I study of aurora A kniase inhibitor MLN8237 in advanced solid tumors: safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations. Clin Cancer Res 2012; 18: 4775-4784.

Product Citation

1. Tomoaki Sobajima, Katarzyna M Kowalczyk, et al. "PP6 regulation of Aurora A–TPX2 limits NDC80 phosphorylation and mitotic spindle size." J Cell Biol. 2023 May 1;222(5):e202205117. PMID: 36897279
2. Bao Y, Zhang S, et al. "Targeting RBM10 deficiency in lung adenocarcinoma." Cancer Res 2023 Feb 28 PMID: 36853175
3. Dammert MA, Br?gelmann J, et al. "MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer." Nat Commun. 2019 Aug 2; 10 (1): 3485. PMID:31375684
4. Laura Tomino, Emily Bopp, et al. "Combinatorial BRD4 and AURKA inhibition is synergistic against preclinical models of Ewing sarcoma." Cancer reports. 11 February 2019.
5. Shaon Parial. "Novel Interaction, Regulation of Phosphorylation and Mitotic Localization of Cell Division Cycle Associated Protein 7 (CDCA7)" York University. 2018.
6. Teke K, Yilmaz H, et al. "Histopathologic and molecular comparative analyses of intravesical Aurora kinase-A inhibitor Alisertib with bacillus Calmette-Guérin on precancerous lesions of bladder in a rat model." Int Urol Nephrol. 2018 Jun 21. PMID:29931492
7. Krulikas LJ, McDonald IM, et al. "Application of Integrated Drug Screening/Kinome Analysis to Identify Inhibitors of Gemcitabine-Resistant Pancreatic Cancer Cell Growth." SLAS Discov. 2018 May 1:2472555218773045. PMID:29742358
8. Joshua Felgenhauer, Laura Tomino, et al. "Dual BRD4 and AURKA Inhibition is Synergistic against MYCN-amplified and nonamplified Neuroblastoma." bioRxiv.2018 Mar.5.
9. Mathison A, Salmonson A, et al."Combined AURKA and H3K9 Methyltransferase Targeting Inhibits Cell Growth By Inducing Mitotic Catastrophe." Mol Cancer Res. 2017 Aug; 15 (8): 984-997. PMID:28442587

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Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	518.92
Cas No.	1028486-01-2
Formula	C₂₇H₂₀ClFN₄O₄
Solubility	≥25.95 mg/mL in DMSO; insoluble in H2O; insoluble in ETOH
Chemical Name	4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid
SDF	Download SDF
Canonical SMILES	COC1=C(C(=CC=C1)F)C2=NCC3=CN=C(N=C3C4=C2C=C(C=C4)Cl)NC5=CC(=C(C=C5)C(=O)O)OC
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment: [1]
Cell lines	TIB-48 and CRL-2396 cells
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37°C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20°C for several months.
Reaction Conditions	>100 nM, 48 hours
Applications	TIB-48 and CRL-2396 cells were treated with MLN8237 at 10 nM, 50 nM, 100 nM, 500 nM and 1.0 μM for 48 h. MLN8237 induced apoptosis at concentrations >100 nM, suggesting that induction of apoptosis is dose-dependent. These results were confirmed by demonstrating an increased level of cleaved PARP in treated TIB-48 and CRL-2396 cells. PARP cleavage was observed even at the concentration of MLN8237 as low as 50 nM.
Animal experiment: [2]
Animal models	Female C.B-17 SCID mice injected with OVCAR-5-pWZL-Luc cells
Dosage form	Oral administration, 20 or 30 mg/kg, once daily (QD) or twice daily (BID)
Applications	The mice (n=16/group) were randomly divided into five treatment groups: 1) vehicle, 2) 20 mg/kg alisertib, 3) 30 mg/kg alisertib, 4) 5 mg/kg paclitaxel and 5) 20 mg/kg alisertib + 5 mg/kg paclitaxel. Tumor growth was monitored by weekly BLI and the log-transformed total flux data showed significantly decreased tumor growth rates in mice treated with alisertib (20 or 30 mg/kg) compared to vehicle-treated mice. Treatment with 20 mg/kg and 30 mg/kg alisertib resulted in 51% and 49% TGI, respectively.
her notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1] Qi W, Spier C, Liu X, et al. Alisertib (MLN8237) an investigational agent suppresses Aurora A and B activity, inhibits proliferation, promotes endo-reduplication and induces apoptosis in T-NHL cell lines supporting its importance in PTCL treatment. Leukemia research, 2013, 37 (4): 434-439. [2] Do T V, Xiao F, Bickel L E, et al. Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion. Oncogene, 2013, 33 (5): 539-549.

Biological Activity

Description	Alisertib (MLN8237) is a selective inhibitor of Aurora A with IC50 of 1.2 nM. It has >200-fold higher selectivity for Aurora A than Aurora B.
Targets	Aurora A
IC50	1.2 nM